Infectious diseases

INTRODUCTION
Infectious diseases
• significantly contribute to the mortality in
• Elderly.
• Immunosuppressed.
• Chronic disease states.
• constitute six of the top 10 causes of mortality in developing
countries abetted by malnutrition & unsanitary living
conditions.

How Microorganisms Cause Disease
• Humans harbor a complex ecosystem of microbial flora.
• Attenuation of normal host defenses  “healthy” microbial flora to
cause pathologic infections.
• Non-commensal organisms with a wide range of virulence.
• Highly infectious microbes produce disease in healthy individuals.

Routes of Entry of Microbes
Vertical transmission  Infection from mother to fetus or
newborn child.
• Placental-fetal transmission during pregnancy in which the
effects on fetal development will depend on when during
gestation the infection occurs (e.g rubella infection during 1st
trimester )
• Transmission during birth (e.g., gonococcus & chlamydia).
• Postnatal transmission in maternal milk (e.g., CMV, HIV,
HBV).

Spread & Dissemination of Microbes
Within the Body

Release From the Body &
Transmission of Microbes
• Person to person via respiratory, fecal-oral, sexual, or
transplacental routes.
• Animal-to-human transmission can occur through direct
contact or ingestion (zoonotic infections)
• Insect or arthropod vectors may passively spread infection
or serve as required hosts for pathogen replication &
development.
• Survival during extended periods in dust, food, or water;

Host-Pathogen Interactions
Host Defenses Against Infection
• Innate & adaptive immune systems are critical to preventing
or eradicating infection.
• Stalemate between host & microbe results in a state of
microbial latency without much pathology.
• Subsequent diminution of host immunity can result in
aggressive reactivation & disease (e.g. EBV, TB)

Immune Evasion by Microbes
• Antigenic variation.
• Resistance to antimicrobial peptides (defensins &
cathelicidins) by inhibiting peptide binding or by
producing proteases to degrade peptides.
• Resistance to phagocyte killing by production of proteins
that kill phagocytes, prevent their migration, or diminish
their oxidative burst.
• Evasion of apoptosis & manipulation of host cell
metabolism which allows replication, enter latency, or
even transform the cell.

Immune Evasion by Microbes
• Resistance to cytokine-/chemokine-/complement-
mediated host defense.
• Evasion of recognition by CD4+ helper T cells &
CD8+ cytotoxic T-cells.
• Downregulation of T-cell responses by exploitation of
immunoregulatory mechanisms.
• ‘Lying low’ by establishing a state of latent infection
in which few if any viral genes are expressed.

Injurious Effects of Host Immunity
• Granulomatous responses can sequester pathogens but can
cause secondary tissue damage & fibrosis with
mycobacterium tuberculosis infection.
• Liver damage following HBV infection is due to the immune
destruction of infected hepatocytes.
• Antibodies directed against bacterial antigens may cross-react
with host molecules (e.g., rheumatic heart disease) or may
form immune complexes that lodge in vascular beds (e.g.,
poststreptococcal glomerulonephritis).
• Chronic inflammation & epithelial injury may lead to
malignancy (e.g., Helicobacter pylori & gastric cancer).

Infections in People With
Immunodeficiencies
Genetic immunodeficiencies
• Antibody deficiencies
– X-linked agammaglobulinemia is associated with Streptococcus pneumoniae,
Haemophilus influenzae, Staphylococcus aureus, rotavirus, & enterovirus
infections.
• Complement proteins:
– Associated with infections due to encapsulated bacteria (e.g., S. pneumoniae
for early complement components & Neisseria meningitidis for late [C5 to C9]
elements).
• Neutrophil function:
– Infections from S. aureus, gram-negative bacteria, & fungi.
• T-cell deficiencies:
– Infections due to intracellular pathogens (e.g.viruses & some parasites); defects
in TH1 generation increase the risk of infections by atypical mycobacteria, &
defects in TH17 generation are associated with chronic mucocutaneous
candidiasis.

Immunodeficiencies
Acquired immunodeficiencies:
HIV annihilation of T-helper cells is associated with a variety of
infections
• Most organisms that infect people with AIDS were common
pathogens before the era of HIV-AIDS
• Uncommon organisms were Kaposi sarcoma herpes virus
[KSHV], cryptococcus, & Pneumocystis.
• Malnutrition also broadly impairs immune defenses.

Immunodeficiencies
Immunosuppression :
• Use of immunosuppressive drugs in organ
transplantation/bone marrow engraftment renders patients
susceptible to virtually all organisms, including common
environmental microbes.
• Hematopoietic stem cell transplant recipients have profound
defects in innate & adaptive immunity during the time that it
takes for the donated stem cells to engraft, & become
susceptible to infection with almost any organism.
• Decline of immune responses can result in reactivation of
latent infections (herpes, TB) & severe pathologic
manifestations.

Immunodeficiencies
Diseases of organs other than the immune system also
render patients susceptible to specific organisms.
• Lack of splenic function in sickle cell disease increases risk of
infection by encapsulated bacteria (S. pneumoniae).
• Patients with cystic fibrosis commonly get respiratory
infections with Pseudomonas.
• Burns destroy skin  exposure to microbes  infection with
pathogens (P. aeruginosa).

Host Damage
• Infectious disease results from the interaction of microbial
virulence characteristics & host immune responses.
• Infectious agents cause damage by the following:
– Entering cells & directly causing cell death.
– Releasing toxins that kill cells at a distance.
– Releasing enzymes that degrade tissue components.
– Damage blood vessels, causing ischemic necrosis.
– Inducing host inflammatory cell responses that directly or
indirectly injure tissues.

Mechanisms of Viral Injury
• Viruses have tissue tropisms that will dictate which tissues will be
injured.
• Determinants of viral tropisms include :
– Binding to specific cell surface proteins
HIV binds to CD4 & the CXCR4 chemokine receptor on T cells.
– Cell type-specific proteases may be necessary to enable
binding
Host protease activation of influenza virus hemagglutinin.
– Cell type-specific transcription factors
JC virus can proliferate only in oligodendroglia.
– Physical barriers, local temperature, & pH
Enteroviruses resist gut acid & enzymes.

Mechanisms of Viral Injury
Once inside cells, viruses cause injury by :
– Direct cytopathic effects
• Inhibiting host DNA, RNA, or protein synthesis
• Producing degradative enzymes or toxic proteins
• Inducing apoptosis
• Damaging the plasma membrane (HIV)
• Lysing cells (rhinoviruses & influenza viruses)
– Inducing an antiviral host immune response
– Cytotoxic T cells or natural killer (NK) cells
• Transformation of infected cells

Mechanisms of Bacterial Injury
Bacterial Virulence
• Virulence genes are frequently clustered together in the
microbe genome as pathogenicity isl&s.
• Plasmids & bacteriophages are mobile genetic elements that
can encode & transfer virulence factors between different
bacteria (e.g., toxins or antibiotic resistance).
• Virulence factor expression may be coordinated by the
secretion of peptides that turn on specific genes in the
population, a process called quorum sensing.
• Communities of bacteria—particularly in association with
artificial surfaces (e.g., catheters & artificial joints)—can form
‘biofilms’.

Bacterial Adherence to Host Cells
• Bacterial adhesins are surface molecules that bind to specific
host cells or matrix
– Bacterial adhesins influence tissue tropisms.
• Pili are filamentous bacterial surface proteins that can also
mediate adhesion & can be targeted by immune responses
– Pilus variation is a mechanism used by Neisseria
gonorrhoeae to escape immune clearance.

Virulence of Intracellular Bacteria
• Intracellular bacteria can kill host cells by rapid replication &
lysis (Shigella & Escherichia coli).
• Intracellular bacteria may permit continued host cell viability
while evading intracellular defenses & proliferating within
endosomes (M. tuberculosis) or cytoplasm (Listeria
monocytogenes).

Bacterial Toxins
Endotoxins (lipopolysaccharide [LPS])
• It is a cell wall component of gram-negative bacteria
composed of a common long-chain fatty acid (lipid A) & a
variable carbohydrate chain (O antigen).
• Low doses of the lipid A component elicit protective
inflammatory cell recruitment & cytokine production.
• Higher doses of the lipid A component contribute to septic
shock, disseminated intravascular coagulation, & adult
respiratory distress syndrome.

Bacterial Toxins
Exotoxins damage host tissues by :
• Enzymes destroy tissue integrity by digesting
structural proteins.
• Exotoxins alter intracellular signaling
• Exotoxins have a binding (B) subunit that delivers a
toxic active (A) component into the cell cytoplasm,
where it modifies signaling pathways to cause cell
dysfunction or death
• e.g. seen in diptheria, anthrax, or cholera.

Bacterial Toxins
Neurotoxins that block neurotransmitter release, causing
paralysis
– e.g., in botulism & tetanus
Superantigens stimulate large numbers of T cells by linking
Tcell receptors with class II MHC molecules on
antigenpresenting cells massive T-cell proliferation &
cytokine release
– e.g., toxic shock syndrome due to S. aureus.

Bacterial Toxins
Endotoxin (lipopolysaccharide [LPS])
• It is a cell wall component of gram-negative bacteria
composed of a common long-chain fatty acid (lipid A) & a
variable carbohydrate chain (O antigen).
• Low doses of the lipid A component elicit protective
inflammatory cell recruitment & cytokine production.
• Higher doses of the lipid A component contribute to
septic shock, disseminated intravascular coagulation, &
adult respiratory distress syndrome.

Sexually Transmitted Infections
• Groups at greater risk includes adolescents,
homosexuals & IV drug users.
• STIs in children, unless acquired during birth, suggest
sexual abuse.
• Transmission requires direct person-to-person contact
because the pathogens do not survive in the
environment.
• Transmission often occurs from asymptomatic persons.
• Infection with one STI-associated organism increases
the risk for additional STIs.
• STI in pregnancy can be spread to the fetus either in
utero or at delivery, resulting in severe damage.

Sexually Transmitted Infections

Spectrum of Inflammatory Responses
to Infection

to Infection
Suppurative (Purulent) Inflammation
• usually caused by pyogenic bacteria,
mostly extracellular gram-positive
cocci & gram- negative rods.
• Increased vascular permeability &
neutrophil recruitment by bacterial
chemoattractants.
• • Lesions vary from tiny
microabscesses to entire lung lobes.
• may resolve without sequelae
(pneumococcal pneumonia) or may
scar (Klebsiella).
Pneumococcal pneumonia with extensive
neutrophilic infiltrate.

to Infection
• Patterns typical for viruses, intracellular
bacteria, spirochetes, intracellular parasites
& helminths.
• The cell type that predominates depends on
the host response to a particular pathogen:
– plasma cells in chancres of primary
syphilis
– lymphocytes in viral infections of the
brain
– macrophages in Myobacterium avium-
intracellulare infections of AIDS
patients.
• Granulomatous inflammation characterized
by accumulation of activated macrophages,
occurs with resistant organisms that evoke a
strong T-cell response
– M. tuberculosis
Secondary syphilis in the dermis with
perivascular lymphoplasmacytic infiltrate &
endothelial proliferation.
Mononuclear & Granulomatous
Inflammation

to Infection
Cytopathic-Cytoproliferative
Reaction
• usually occurs in viral
Infections.
• there is cell proliferation &
necrosis with sparse
inflammation.
• Other features include
– inclusion bodies (herpes virus)
– fused cells (measles viruses)
– blisters (herpesviruses)
– warty excrescences
(papillomaviruses).
A herpes virus blister showing glassy
intranuclear viral inclusion bodies.
Herpes virus blister in mucosa

to Infection
Tissue Necrosis
• Caused by
– rampant viral infections
• Fulminant HBV infection
– secreted bacterial toxins
• Clostridium perfringens
– direct protozoan cytolysis
of host cells
• Entamoeba histolytica
• There is severe tissue
necrosis in the absence of
inflammation. C. perfringens-induced necrosis

to Infection
Chronic Inflammation &
Scarring
• Outcomes range from
complete healing to
scarring.
• Excessive scarring can cause
dysfunction.
– the “pipestem” fibrosis of the
liver or fibrosis of the bladder
wall caused by schistosomal
eggs
• Inflammation can be severe
despite a paucity of
organisms.
– M. tuberculosis
Schistosoma haematobium infection of the
bladder with numerous calcified eggs &
extensive scarring

Special Techniques for Diagnosing
Infectious Agents
• Routine H&E stained sections.
– CMV inclusion bodies, C&ida & Mucor, most protozoans, & all helminths
• Special stains that take advantage of particular cell wall characteristics or coats
– Gram, acid-fast, silver, mucicarmine, & Giemsa stains.
• Cultures of fluids/lesional tissues may be performed to speciate organisms &
to determine drug sensitivity.
• Antibody titers to specific pathogens.
– IgM antibodies suggest an acute infection, whereas IgG antibodies suggest
something more remote.
• Nucleic acid amplification tests (PCR, transcription-mediated amplification
– Diagnosis of M. tuberculosis, Neisseria gonnorrhoeae, & Chlamydia
trachomatis.
– Quantification of HIV, HBV, & HCV to monitor response to treatment.

Viral Infections - Acute (Transient) Infections
Measles
• RNA paramyxovirus transmitted by respiratory
droplets.
• Initial replication is within upper respiratory
epithelial cells local lymphoid tissue 
systemically.
• Koplik spots - ulcerated oral mucosal lesions
near Stensen ducts.
• Warthin-Finkeldey cells - multinucleated giant
cells with eosinophilic inclusion bodies
• Marked lymphoid follicular & germinal center
hyperplasia.
• Infections - croup, pneumonia, diarrhea,
keratitis & encephalitis.
• Late Cx - Subacute sclerosing panencephalitis
& inclusion body encephalitis
Warthin-Finkeldey cells

Mumps
• Paramyxovirus spread by respiratory droplets.
• Initial replication is lymph nodes draining the upper respiratory
tracthematogenous spread to salivary gl&s & other sites -
testes, ovary, pancreas, & CNS.
• Parotitis  Desquamation, edema, & inflammation in salivary
gl& ductal epithelium swelling & pain.
• Aseptic meningitis is the most common extrasalivary gl&
complication.
• Orchitis - swelling contained within the tunica albuginea 
compromised vascular supply  infarction.

Poliovirus Infection
• Spherical, unencapsulated RNA enterovirus transmitted by the
fecal-oral route.
• The virus infects via CD155, a surface molecule not present in
other species.
• Multiplication in intestinal mucosa & lymph nodes  transient
viremia & fever;
• Systemic viremia/retrograde transport via motor neurons 
replication  CNS involvement  muscular paralysis/bulbar
poliomyelitis.
• Antiviral antibodies control the disease.

West Nile Virus
• Arthropod-borne flavivirus (arbovirus)  Dengue & Yellow fever.
• Transmitted by mosquitos, birds , blood transfusion, organ transplant,
breast milk & transplacentally.
• Initial replication occurs in skin dendritic cellslymph nodes for
further expansion  subsequent hematogenous spread can lead to
CNS neuronal infection.
• CNS complications - meningitis, encephalitis, meningoencephalitis.
• Immunosuppressed & elderly individuals are at greatest risk.
• Rare complications - hepatitis, myocarditis, or pancreatitis.

Viral Hemorrhagic Fever (Ebola, Marburg &
Lassa)
• Systemic infection caused by enveloped RNA viruses from four
different families (arenaviruses, filoviruses, bunyaviruses, &
flaviviruses).
• Manifestations range from mild, acute disease (fever, headache,
rash, myalgia, neutropenia, & thrombocytopenia) to severe, life-
threatening hemodynamic deterioration & shock.
• Infect endothelial cells  2º hemorrhagic manifestations to
endothelial/platelet dysfunction.
• Macrophage & dendritic cell  profound cytokine release.

Viral Infections - Latent Infections (HHV)
• Latency is defined as the persistence of viral genomes that do not
produce infectious virus infarction.
• Reactivation of the latent virus  dissemination +/-tissue injury.
• Human herpes virus are large, encapsulated double-stranded
DNA viruses.
• 3 subgroups are defined by the most common infected cell & the
site of latency :-
– α-Group infects epithelium & produces latent infections of neurons
• HSV-1, HSV-2 & VZV
– β-Group infects lymphocytes & can be latent in a variety of cell types.
• CMV, HHV-6 & HHV-7.
– γ-Group causes latency in lymphoid cells
• EBV & KSHV/HHV-8.

Herpes Simplex Viruses
• replicates in skin & mucous membranes at the site of initial inoculation
(usually oropharynx/genitals), causing vesicular lesions.
• epithelial infection  sensory neurons  retrograde axonal transport to the
sensory neuron ganglia (latent infection)
• During reactivation, virus spreads from regional ganglia back to skin or mucous
membranes.
• Lesions range from self-limited cold sores & gingivostomatitis (HSV-1) to
genital sores (HSV-2) to life threatening disseminated visceral infections
(hepatitis & bronchopneumonitis) and encephalitis
• Classic lesions include large, pink-purple, virion-containing intranuclear
inclusions (Cowdry type A inclusions) and inclusion-bearing multinucleated
syncytia.

Herpes Simplex Viruses
• HSV-1 is also the major infectious
cause of corneal blindness in the
US.
• Herpes epithelial keratitis reflects
virus-induced cytolysis of the
superficial corneal epithelium.
• Herpes stromal keratitis results in
– mononuclear cell infiltrates
around keratinocytes and
endothelial cells.
– Subsequent
neovascularization, scarring,
and corneal opacification
leads to blindness.
Herpes epithelial keratitis
Herpes stromal keratitis

Varicella-Zoster Virus
• transmitted by aerosols, disseminates hematogenously &
causes widespread vesicular skin lesions.
• Acute VZV infection causes chickenpox & reactivation of latent
VZV causes shingles/herpes zoster.
• VZV infects mucous membranes, skin, and neurons, establishing a
latent infection in sensory ganglia.
• causes interstitial pneumonia, encephalitis, transverse myelitis, &
necrotizing visceral lesions in immunocompromised hosts.

Shingles occurs when latent
VZV in dorsal root ganglia
reactivates, infecting
sensory nerves that carry
viruses to the skin &
causing painful vesicular
lesions, typically in a
dermatomal distribution.
Dorsal root ganglion with varicella-zoster virus
infection showing ganglion cell necrosis &
associated inflammation

• Skin lesions evolve rapidly
from macules to vesicles,
classically resembling “a
dew drop on a rose petal.”
• Histologically vesicles
contain epithelial cell
blisters and intranuclear
inclusions.
Skin lesion of chickenpox (varicella-zoster
virus) with intraepithelial vesicle.
'dew drop on rose petal' appearance.

Cytomegalovirus
• transmitted in breast milk, respiratory droplets, blood, and saliva
and can have transplacental, venereal, feco-oral, transfusion, or
organ transplantation.
• mononucleosis-like syndrome (fever, atypical lymphocytosis,
lymphadenopathy & hepatosplenomegaly).
• cause life-threatening colitis/pneumonitis, hepatitis, chorioretinitis,
and meningoencephalitis in AIDS/immunosuppressed patients.
• Causes cytomegalic inclusion disease (CID) - intrauterine growth
retardation, hemolytic anemia, jaundice, encephalitis, deafness &
mental retardation.

Cytomegalovirus
• CMV infection causes
marked cellular
enlargement, with
characteristic large
intranuclear inclusions
surrounded by a clear halo,
and smaller basophilic
cytoplasmic inclusions. A large cell containing a large basophilic
intranuclear “owl’s eye” and intracytoplasmic
inclusion bodies.

Viral Infections - Chronic Productive Infections
• In some infections the immune system cannot eliminate the virus,
thus resulting in persistent viremia.
• High mutation rates may be a mechanism to evade the immune
system.
• e.g. HIV, HBV

Viral Infections - Transforming Viral Infections
Epstein-Barr Virus
• Occur through close contact, including saliva, blood or venereal
transmission.
• Begins in nasopharyngeal and oropharyngeal epithelial cells 
infection of B cells in underlying lymphoid tissues  virus binds
to CD21 (the complement C3d receptor).
• Has a productive lytic infection, releasing more virions.
• Establishes a latent infection via genes that can induce B-cell
proliferation as well as production of heterophile antibodies
which can agglutinate sheep or horse erythrocytes.

Viral Infections - Transforming Viral Infections
Epstein-Barr Virus
• Causes infectious mononucleosis characterized by fever, fatigue,
sore throat, lymphocytosis, generalized lymphadenopathy, &
splenomegaly; hepatitis & rash.
• Symptoms are secondary to the host immune response:
– CD8+ cytotoxic T cells (the atypical lymphocytes seen in the
– blood) recognize and lyse EBV-infected B cells.
– Reactive proliferation of these T cells leads to lymphadenopathy and
splenomegaly.
• Persistence of EBV in a small population of latently infected cells can result in
late reactivation and B-cell proliferation.
• In immunocompromised individuals, EBV is associated with B-cell lymphoma &
also contributes to some cases of Burkitt lymphoma.

Viral Infections - Transforming Viral
Infections
Atypical lymphocytes in infectious mononucleosis.
Epstein-Barr Virus

Bacterial Infections - Gram-Positive Bacterial Infections
Staphylococcal Infections
• Organisms are pyogenic (pus-forming) cocci that grow in clusters
and are distinctive for local destructiveness.
• cause a variety of skin infections (boils, carbuncles, impetigo),
osteomyelitis, pneumonia, endocarditis, food poisoning & toxic
shock syndrome.
• Less virulent ones cause opportunistic infections
– Staphylococcus epidermidis in IV drug abusers, patients with
catheters/prosthetic heart valves.
– Staphylococcus saprophyticus causes UTI

Staphylococcal Infections
Virulence factors include the following:
– Surface proteins that allow host cell adherence.
– Enzymes that degrade host proteins, promoting invasion and tissue
destruction.
– Toxins that damage host cell membranes (hemolysins) or induce skin
sloughing (exfoliative toxins), vomiting (enterotoxins), or shock
(superantigens).
– Antibiotic resistance is a growing problem with S. aureus
– infections.
• methicillin-resistant S. aureus (MRSA) can now be a virulent community-acquired
infection.

Streptococcal and Enterococcal Infections
• Cocci that grow in pairs or chains.
• Classified by their pattern of hemolysis on blood agar
– β (complete or clear hemolysis)
– α (partial or green hemolysis)
– γ (no hemolysis, rarely pathogenic)
• β-Hemolytic streptococci are grouped by their carbohydrate
(Lancefield) antigens:
– Group A (Streptococcus pyogenes) causes pharyngitis, scarlet fever,
erysipelas, impetigo, rheumatic fever, toxic shock syndrome, necrotizing
fasciitis, and glomerulonephritis.
– Group B (Streptococcus agalactiae) colonizes the female genital tract and
causes chorioamnionitis in pregnancy; neonatal sepsis and meningitis.

• α-Hemolytic streptococci include S. pneumoniae, a common
cause of adult community-acquired pneumonia and meningitis.
• Viridans-group includes both α- and γ-hemolytic streptococci that
are normal oral flora but are common causes of endocarditis
• Streptococcus mutans is the major cause of dental caries
(metabolizes sucrose to lactic acid which demineralizes tooth
enamel).
• Enterococci cause endocarditis and urinary tract infections; many
are antibiotic resistant.
• Enterococci have an antiphagocytic capsule and produce enzymes
that degrade host tissues.
• Streptococcal infections are characterized by diffuse interstitial
neutrophilic infiltrates with minimal host tissue destruction

Streptococcal virulence factors include the following:
– Capsules that resist phagocytosis (S. pyogenes and S.pneumoniae).
– M proteins that inhibit complement activation (S. pyogenes).
– Exotoxins that cause fever and rash (S. pyogenes) in scarlet Fever.
– Pneumolysin destroys host-cell membranes and damages tissue (S.
pneumoniae).

Diphtheria
• caused by Corynebacterium diptheriae, a slender gram-positive
rod with clubbed ends; it is passed as an aerosol or through skin
exudates.
• life-threatening disease characterized by an oropharyngeal
fibrinosuppurative exudate; C. diphtheriae growth in this
membrane elaborates an exotoxin that injures heart, nerves, and
other organs.
• Toxin is a phage-encoded two-part (A-B) toxin that blocks host
protein synthesis.
– The B fragment binds to the cell surface and facilitates entry of the A
subunit.
– the A subunit blocks protein synthesis by adenosine diphosphate (ADP)
ribosylation (and inactivation) of elongation factor-2.

Listeriosis
• caused by L. monocytogenes - a gram-positive, facultative
intracellular bacillus.
• causes sepsis and meningitis in elderly & immunosuppressed
people and placental infections in pregnant women with
consequent neonatal infections.
• express leucine-rich proteins called internalins that bind epithelial
E-cadherin and promote internalization.
• bacillus then uses listeriolysin O and two phospholipases to
degrade the phagolysosome membrane and escape into the
cytoplasm.
• Resting macrophages internalize but do not kill Listeria;
macrophages activated by interferon-γ effectively phagocytize
and kill the bacterium.

Anthrax
• Bacillus anthracis is a spore-forming, gram-positive bacillus
prevalent in animals having contact with spore-contaminated soil.
• Humans contract anthrax through exposure to contaminated
animal products or powdered spores (a biologic weapon).
• 3 major anthrax syndromes are known; in all cases, lesions are
characterized by necrosis with neutrophil and macrophage
exudates:
– Cutaneous: Painless, pruritic papules that become edematous vesicles
followed by a black eschar.
– Inhalation: Rapidly leads to sepsis, shock, and frequently death .
– GI: Contracted by eating contaminated meat; causes severe, bloody
diarrhea and often death

Anthrax
• Toxin is composed of a B subunit
involved in toxin endocytosis and
A subunits of two different types:
– Edema factor converts
adenosine triphosphate (ATP)
to cAMP, which causes
cellular water efflux.
– Lethal factor is a protease
that causes cell death
Bacillus anthracis in the subcapsular sinus of a
hilar lymph node of a patient who died of
inhalational anthrax

Nocardia
• aerobic, gram-positive bacteria growing in branched chains; they
also stain with modified acid-fast protocols (Fite- Faraco stain)
• are found in soil and cause opportunistic infections in
immunocompromised hosts.
• Nocardia asteroides causes indolent respiratory infections often
with CNS dissemination;
• Nocardia brasiliensis infects the skin.
• Nocardia elicit suppurative responses, surrounded by granulation
tissue and fibrosis.

Bacterial Infections - Gram-Negative Bacterial Infections
Neisserial Infections
• aerobic, gram-negative diplococci
• they usually have stringent in vitro growth.
• requirements (e.g., sheep blood-enriched [“chocolate”] agar).
• N. meningitidis is an important cause of bacterial meningitis,
particularly in children younger than age 2; there are 13 different
serotypes.
– Bacteria colonize the oropharynx (10% of the population is colonized at any
one time) and are spread by respiratory droplets.
– Meningitis occurs when people encounter serotypes to which they are not
previously immune (e.g., in military barracks or college dormitories).
• Neisseria gonorrhoeae is the second most common sexually transmitted
bacterial infection in the US

Neisserial Infections
• Neisseria gonorrhoeae is the second most common sexually
transmitted bacterial infection in the US (after Chlamydia).
– In males it causes symptomatic urethritis; in women it is often
asymptomatic and can lead to pelvic inflammatory disease, infertility, and
ectopic pregnancy.
– Disseminated adult infections cause septic arthritis & hemorrhagic rash.
– Neonatal infections cause blindness and, rarely, sepsis.
• Virulence factors include a capsule that inhibits opsonization &
antigenic variation to escape the immune response:
– Adhesive pili undergo genetic recombination.
– Outer membrane adhesive OPA proteins (so-called because they make
colonies opaque) undergo 5-nucleotide frameshifts.
– Host defects in complement lead to more severe infections.

Pertussis
• caused by Bordetella pertussis, a gram-negative coccobacillus
• it is a highly communicable illness characterized by paroxysms of
violent coughing (whooping cough).
• Coordinated expression of virulence factors is regulated by the
Bordetella virulence gene (bvg) locus:
– Hemagglutinin binds to respiratory epithelium carbohydrates
and macrophage Mac-1 integrins.
– Pertussis toxin ADP ribosylates and inactivates guanine
nucleotide-binding proteins; G proteins cannot transduce
signals, and bronchial epithelium cilia are paralyzed.
• Infection causes laryngotracheobronchitis with mucosal erosion &
mucopurulent exudates associated with striking peripheral
lymphocytosis.

Pseudomonas Infection
• caused by Pseudomonas aeruginosa, an opportunistic aerobic,
gram-negative bacillus.
• frequently seen in patients with cystic fibrosis, burns, or
neutropenia and is a common hospital-acquired infection.
• It also causes corneal keratitis in contact wearers and external
otitis (swimmer’s ear) in normal hosts.
• Pseudomonas pneumonia can cause extensive tissue necrosis by
vascular invasion with subsequent thrombosis.
• Skin infections give rise to well-demarcated necrotic and
hemorrhagic skin lesions, ecthyma gangrenosum.

Pseudomonas Infection
• Virulence factors include the following:
– Pili and adherence proteins that bind to epithelial cells & lung mucin.
– Endotoxin that cause gram-negative sepsis and disseminated
– intravascular coagulation.
– Exotoxin A that inhibits protein synthesis by the same mechanism as
diphtheria toxin.
– Phospholipase C that lyses red cells and degrades surfactant & an elastase
that degrades IgG and extracellular matrix (ECM).
– Iron-containing compounds that are toxic to endothelium.
– In patients with cystic fibrosis the organism secretes an exopolysaccharide
(alginate) that forms a slimy biofilm that protects bacteria from antibodies,
complement, phagocytes & antibiotics.

Plague
• Yersinia is a gram-negative, facultative intracellular bacterium
with three clinically important species:
– Yersinia pestis causes plague; it is transmitted from rodents to humans by
aerosols or fleabites.
– Yersinia enterocolitica and Yersinia pseudotuberculosis cause fecaloral
transmitted ileitis and mesenteric lymphadenitis.
• Yersinia proliferate in lymphoid tissues.
• Causes massive lymph node enlargement (buboes), pneumonia,
and sepsis, with massive bacterial proliferation, tissue necrosis,
and neutrophilic infiltrates.

Plague
Virulence factors include the following:
• Yersinia toxins (called Yops) that are injected into host phagocytes
by a syringe- like mechanism; the toxins block phagocytosis and
cytokine production.
• A biofilm that obstructs the flea GI tract, forcing it to regurgitate
before feeding and thus ensuring infection.

Chancroid and Granuloma Inguinale
• Chancroid (soft chancre) is an acute, venereal, ulcerative genital
infection caused by Haemophilus ducrey which is most common in
Africa & Southeast Asia; the ulcerations probably serve as
important cofactors in HIV transmission.
• Granuloma inguinale is a sexually transmitted disease caused by
Klebsiella granulomatis, a minute, encapsulated coccobacillus.
• Infection begins as a papule on the genitalia or extragenital sites
• (oral mucosa or pharynx) that ulcerates & granulates to form a
• soft, painless mass, with prominent epithelial hyperplasia at the
• borders.
• • Left untreated, the lesion may scar and cause urethral, vulvar, or
• anal strictures; it is also associated with lymphatic scarring and
• lymphedema of the external genitalia.

Chancroid and Granuloma Inguinale
• Chancroid (soft chancre) is an acute, venereal, ulcerative genital
infection caused by Haemophilus ducrey which is most common in
Africa & Southeast Asia; the ulcerations probably serve as
important cofactors in HIV transmission.
• Granuloma inguinale is a sexually transmitted disease caused by
Klebsiella granulomatis, a minute, encapsulated coccobacillus.
• Infection begins as a papule on the genitalia or extragenital sites
(oral mucosa or pharynx) that ulcerates & granulates to form a
soft, painless mass, with prominent epithelial hyperplasia at the
borders.
• Left untreated, the lesion may scar and cause urethral, vulvar, or
anal strictures; it is also associated with lymphatic scarring and
lymphedema of the external genitalia.

Bacterial Infections - Mycobacteria
Tuberculosis
• caused by M. tuberculosis & transmitted person to person as an
aerosol and increasingly is multidrug resistant.
• Infection represents only the presence of organisms and in most
cases does not cause clinical disease.
• Virulence is based on the properties of its cell wall.
• Host recognition of tuberculosis organisms involves multiple
innate pathogen-associated molecular patterns (lipoproetins &
glycolipids) triggering Toll-like receptors (TLR)-2 and -9.
• Outcomes of infection depend on host immunity.

Tuberculosis
• Infection leads to the induction of a TH1-mediated delayed
hypersensitivity response that activates macrophages.
– Promote endocytosis and killing via nitric oxide (NO) and/or autophagy.
– Promote cytocidal activity through tumor necrosis factor & defensin
production.
– Surround microbes with granulomatous inflammation.
• Caseating granulomas are characteristic; central necrosis is
surrounded by lymphocytes and activated macrophages.
• T-cell immunity to mycobacteria can be detected by a tuberculin
skin test which signifies only prior T-cell sensitization to
mycobacterial antigens and does not discriminate infection and
disease.

Tuberculosis
• Granulomas formed in response to infection typically involve the
lung apex and draining lymph node  Ghon complex.
• Eventual control of the infection leaves behind only a small
residua  a tiny fibrocalcific nodule at the site where viable
organisms may remain within granulomas, dormant for decades.
• 5% of primary infections are symptomatic, with lobar
consolidation, hilar adenopathy & pleural effusions.
– Rarely, hematogenous spread leads to tuberculous meningitis
– & systemic miliary tuberculosis.
– >50% of patients with severe immune deficiency will have extrapulmonary
involvement.

Tuberculosis
• Secondary tuberculosis occurs in a previously exposed host,
classically involving the lung apices.
• If immunity wanes, the infection can reactivate to produce communicable
disease with substantial morbidity & mortality.
• Classically, because of prior T-cell sensitization, there is more tissue damage
with apical pulmonary cavitation & increased systemic manifestations with
low-grade fever, night sweats & weight loss.
• HIV is associated with an increased risk of tuberculosis, due to
diminished T-cell immunity.
• Diagnosis of tuberculosis can be made :
– Identifying acid-fast bacilli in sputum or tissue
– Culture from sputum or tissue (allows drug sensitivity testing)
– Polymerase chain reaction (highly sensitive)

Mycobacterium Avium Complex
• These common environmental bacteria cause widely
disseminated infections in immunocompromised hosts
characterized by abundant acid-fast organisms within
macrophages.

Leprosy
• slowly progressive infection caused by Mycobacterium leprae
affecting skin & peripheral nerves with resultant deformities.
• Inhaled M. leprae are phagocytized by pulmonary macrophages
& disseminated hematogenously; however, they replicate only in
cooler tissues of the periphery.
• Virulence is based on the properties of its cell wall.
• 2 patterns of disease depending on the host immune response:
– Tuberculoid leprosy
– Lepromatous (anergic) leprosy

Leprosy
• Tuberculoid leprosy
– Associated with a TH1
response (IFN-γ), with
extensive granulomatous
inflammation with few bacilli.
– Clinically there are insidious,
dry, scaly skin lesions lacking
sensation, with asymmetric
peripheral nerve involvement.
– Local anesthesia with skin and
muscle atrophy increases the
risk of trauma with chronic
ulcers, and autoamputation of
digits.

Leprosy
• Lepromatous (anergic) leprosy
– Associated with a relatively
ineffective TH2 response, with large
collections of lipid-laden
macrophages overstuffed with
bacilli.
– Clinically there are disfiguring
cutaneous thickening and nodules,
with nervous system damage due to
mycobacterial invasion into
perineural macrophages and
Schwann cells.
– The testes are usually extensively
involved leading to sterility.

Bacterial Infections - Spirochetes
Syphilis
• caused by Treponema pallidum, transmitted venereally or
transplacentally (congenital syphilis).
• A TH1 delayed-type hypersensitivity response with macrophage
activation appears important in reining in the infection, but can
also be the cause of disease manifestations.
• Primary syphilis occurs about 3 weeks after contact:
– A firm, nontender, raised, red lesion (chancre) forms on the penis, cervix,
vaginal wall, or anus; this will heal even without therapy.
– Treponemes are plentiful (visualizable with silver or immunofluorescent
stains) at the chancre surface; there is an exudate composed of plasma
cells, macrophages & lymphocytes, with a proliferative endarteritis.
– Treponemes spread lymphohematogenously throughout the body even
before the chancre appears.

• Chancre contains an
intense infiltrate of
plasma cells, with
scattered macrophages
and lymphocytes

Syphilis
• Secondary syphilis occurs 2 to 10 weeks later in 75% of untreated
patients, due to spread and proliferation of spirochetes in skin
(including palms and soles) and mucocutaneous tissues
(especially mouth).
– Superficial lesions with erosions are painless and contain infectious
spirochetes. Mucocutaneous lesions show plasma cell infiltrates and
obliterative endarteritis.
– Lymphadenopathy, mild fever, malaise, and weight loss are common.

Syphilis
• Tertiary syphilis occurs in one third of untreated patients, after a
long latent period (>5 years).
– Cardiovascular syphilis (>80% of tertiary syphilis) results in aortitis (due to
endarteritis of the aortic vasa vasorum) with aortic root and arch
aneurysms and aortic valve insufficiency.
– Neurosyphilis can be symptomatic (meningovascular disease, tabes
dorsalis, or diffuse brain parenchymal disease, so-called general paresis) or
asymptomatic (cerebrospinal fluid [CSF] abnormalities only, with
pleocytosis, increased protein, and decreased glucose).
– “Benign” tertiary syphilis is associated with necrotic, rubbery masses
(gummas due to delayed-type hypersensitivity to the organisms), which
form in various sites (bone, skin, oral mucosa).

• Gummas have centers of
coagulated, necrotic
material and margins
composed of plump,
palisading macrophages
and fibroblasts
surrounded by large
numbers of mononuclear
leukocytes, chiefly plasma
cells.
Trichrome stain of liver shows a gumma (scar),
stained blue, caused by tertiary syphilis (the
hepatic lesion is also known as hepar lobatum

Syphilis
• Congenital syphilis usually occurs when the mother has primary or
secondary syphilis.
– Intrauterine or perinatal death will occur in 50% of untreated cases.
– Early (infantile) congenital syphilis includes nasal discharge, a bullous rash
with skin sloughing, hepatomegaly, and skeletal abnormalities (nose and
lower legs are most distinctive). Diffuse lung or liver fibrosis can also occur.
– Late (tardive) manifestations include notched central incisors, deafness,
and interstitial keratitis with blindness (Hutchinson triad).

Syphilis
Serologic tests
• Treponemal antibody tests measure antibodies reactive with
T.Pallidum.
• Non-treponemal tests (venereal disease research laboratory
[VDRL], rapid plasma reagin [RPR]) measure antibody to
cardiolipin, a phospholipid in treponemes and normal tissues.
• Both tests become positive approximately 6 weeks after infection
but are only moderately sensitive (70% to 85%) for primary
syphilis; they are >95% sensitive for secondary syphilis.
– Nontreponemal test may become negative with time or treatment, but
treponemal antibody tests remain positive and are very sensitive for
tertiary and latent syphilis.

Lyme Disease
• Caused by Borrelia burgdorferi transmitted from rodents by
Ixodes ticks.
• B. burgdorferi evades antibody-mediated immunity through
antigenic variation.
• The bacterium does not make toxins; rather the pathology
associated with infection is due to host immune responses.
• A distinctive feature of Lyme arthritis is an arteritis resembling
that is seen in lupus erythematosus.

Lyme Disease
3 stages.
• Stage 1 (weeks):
Spirochetes multiply at the site of the tick bite, causing an expanding erythema,
often with a pale center (erythema chronicum migrans), fever, and
lymphadenopathy.
• Stage 2 (weeks to months):
Spirochetes spread hematogenously, causing secondary skin lesions,
lymphadenopathy, migratory joint and muscle pain, cardiac arrhythmias, and
meningitis.
• Stage 3 (years):
• Chronic and occasionally destructive arthritis; less commonly there is
encephalitis and polyneuropathy.

Bacterial Infections - Anaerobic Bacteria
• These organisms normally reside in niches with low oxygen
tension
– intestine, vagina, oral recesses
• They cause disease when they disproportionately expand
– Clostridium difficile colitis following antibiotic treatment or when
introduced into sterile sites.
• Environmental anaerobes also cause disease.
– tetanus, botulism

Bacterial Infections - Abscesses Caused by Anaerobes
• In head and neck abscesses, Prevotella and Porphyromonas are
the usual anaerobes, whereas S. aureus and S. pyogenes are
typical facultative aerobes.
• In abdominal abscesses, Bacteroides fragilis, Peptostreptococcus
& Clostridium species are the common anaerobes, typically
admixed with facultative E. coli.
• In genital tract abscesses in women, the anaerobes include
Prevotella species, often mixed with facultative E. coli or S.
agalactiae.
• Anaerobic abscesses are typically foul smelling and poorly
circumscribed but otherwise pathologically resemble other
pyogenic infections.

Bacterial Infections - Clostridial Infections
Gram-positive bacillus anaerobes that produce spores in the soil.
• C. perfringens and Clostridium septicum cause cellulitis and
muscle necrosis in wounds (gas gangrene), food poisoning, and
small bowel infection in ischemic or neutropenic patients.
– C. perfringens secretes 14 toxins, the most important being α-toxin which
including phospholipase C that degrades erythrocyte, muscle, and platelet
cell membranes & sphingomyelinase that causes nerve sheath damage.
– C. perfringens enterotoxin lyses GI epithelial cells & disrupts tight junctions,
causing diarrhea.
– Gas gangrene exhibits marked edema and enzymatic necrosis of involved
tissues; fermentation gas bubbles, hemolysis, & thrombosis with minimal
inflammation are also characteristic.

• Clostridium tetani in wounds (or the umbilical stump of newborns)
releases a neurotoxin (tetanospasmin) that causes tetanus
convulsive contractions of skeletal musclesby blocking release
of γ-aminobutyric acid, a neurotransmitter that inhibits motor
neuron activity.
• Clostridium botulinum grows in canned foods & it releases a
neurotoxin that causes flaccid paralysis of respiratory and skeletal
muscles (botulism) by blocking acetylcholine release.
– Botulism toxin (Botox) is used in cosmetic surgery for its ability to paralyze
strategically selected facial muscles.

• C. difficile overgrows other intestinal flora in antibiotic-treated
patients and releases two glucosyl transferase toxins, causing
pseudomembranous colitis.
– Toxin A stimulates chemokine production to recruit leukocytes.
– Toxin B (used for diagnosing C. difficile infections) causes cytopathic effects
in cultured cells.

Bacterial Infections - Obligate Intracellular Bacteria
Chlamydial Infections
C. trachomatis exists in two forms:
• A metabolically inactive but infectious sporelike elementary
body (EB). The EB is internalized by receptor-mediated
endocytosis.
• Inside host cell endosomes the EB differentiates into the
metabolically active reticulate body (RB); the RB replicates to
form new EB for release.

Specific C. trachomatis diseases are caused by particular
serotypes:
• Trachoma, an ocular infection of children caused by serotypes A,
B & C.
• Urogenital infections and conjunctivitis caused by serotypes D
to K.

Lymphogranuloma venereum
• Serotypes L1, L2, and L3 is a sporadic genital infection in the United
States and Western Europe.
• It is endemic in parts of Asia, Africa, the Caribbean & South America.
• 2-6weeks after infection, organism growth and host immune
response in draining lymph nodes lead to painful adenopathy.
• Lesions contain a mixed granulomatous and neutrophilic response
with irregular foci of necrosis (stellate abscesses);
• Chlamydial inclusions can be seen in epithelial or inflammatory cells.

Rickettsial Infections
• caused by gram-negative bacilli transmitted by arthropod
vectors.
• primarily infect endothelial cells, causing endothelial swelling,
thrombosis, and vessel wall necrosis.
• Vascular thrombosis and increased permeability cause
hypovolemic shock, pulmonary edema, and CNS manifestations.
• NK cell and cytotoxic T-cell responses are necessary to contain
and eradicate infections.

• Epidemic typhus (Rickettsia prowazekiiis) transmitted by body lice.
– Lesions range from a rash with small hemorrhages to skin necrosis and
gangrene with internal organ hemorrhages.
– CNS typhus nodules show microglial proliferations with T-cell & macrophage
infiltration.
• Rocky Mountain spotted fever (Rickettsia rickettsii) transmitted by
dog ticks.
– A hemorrhagic rash extends over the entire body, including the palms of the
hands & soles of the feet.
– Vascular lesions in the CNS may involve larger vessels & produce
microinfarcts.
– Non-cardiogenic pulmonary edema is the major cause of death.

• Ehrlichiosis is transmitted by ticks.
• The bacteria predominantly infects neutrophils (Anaplasma
phagocytophilum and Ehrlichia ewingii) or macrophages
(Ehrlichia chaffeensis) with characteristic intracytoplasmic
inclusions (morulae).
• Infection is characterized by fever, headache, and malaise,
progressing to respiratory insufficiency, renal failure & shock.

Fungal Infections
• Superficial and cutaneous mycoses:
– Common, limited to superficial keratinized layers of skin, hair, and nails.
• Subcutaneous mycoses:
– Involve skin, subcutaneous tissues, and lymphatics and rarely
disseminate
• Endemic mycoses:
– Caused by dimorphic fungi, capable of causing serious systemic illness in
healthy individuals
• Opportunistic mycoses:
– Can cause life-threatening infections in immunocompromised hosts or in
patients with vascular catheters or prosthetic devices

Fungal Infections - Yeast
Candidiasis
• Candida species are part of the normal flora of the skin, mouth, and GI tract
– they occur as yeast and pseudohyphal forms.
• Candida causes superficial infections in healthy individuals; disseminated
visceral infections in neutropenic patients occur when skin or mucosal
barriers are breached.
• Candida virulence factors include the following:
– Adhesins that mediate binding to host cells.
– Enzymes that contribute to invasiveness.
– Catalases that aid intracellular survival by resisting phagocyte oxidative killing.
– Adenosine that blocks neutrophil degranulation and oxygen radical production.
– Ability to grow as biofilms on devices, thereby frustrating immune responses and
antifungal agents.

Candidiasis
• Innate and T-cell responses are important for protection:
– Neutrophil and macrophage phagocytosis and oxidative killing are the first-
line defense; these are induced as a TH17 response after Candida β-1,3-
glucan engages Dectin-1 on dendritic cells and promotes interleukin (IL)-6
and IL-23 production.
– Yeast forms induce a protective TH1 response; filamentous forms tend to
induce a nonprotective TH2 response.
• Superficial infections of the mouth and vagina are most common, producing
superficial curdy white patches.
• Chronic mucocutaneous candidiasis occurs in persons with AIDS, with defective
T-cell immunity, or with polyendocrine deficiencies (hypoparathyroidism,
hypoadrenalism, and hypothyroidism).
• Severe, invasive candidiasis occurs via bloodborne dissemination in neutropenic
persons; typically, microabscesses (with fungi in the center) are surrounded by
areas of tissue necrosis.

Cryptococcosis
• encapsulated yeast.
– in tissues the capsule stains bright red with mucicarmine
– in CSF it is negatively stained with India ink.
– A capsular polysaccharide (glucuronoxylomannan) inhibits phagocytosis, leukocyte
migration, and inflammatory cell recruitment.
– Regular alteration in the size and structure of the capsule polysaccharide allows immune
evasion.
– Laccase, an enzyme that induces formation of a melaninlike pigment with antioxidant
properties.
– Enzymes that degrade fibronectin and basement membrane proteins and aids in tissue
invasion.
Mucicarmine stain of cryptococci (staining red) in a
Virchow- Robin perivascular space of the brain
(soap-bubble lesion).

Bacterial Infections - Fungal Infections
Cryptococcosis
• In healthy individuals C. neoformans can form solitary
pulmonary granulomata (with reactivation if immunity wanes)
and rarely causes meningoencephalitis.
• It presents as an opportunistic infection in patients with AIDS,
leukemia or lymphoid malignancies, lupus, sarcoidosis, or organ
transplants, or those receiving high-dose corticosteroids.
– In such patients the major lesions involve the CNS, occurring as gray
matter cysts (“soap bubble lesions”), occasionally with no inflammatory
response.

Fungal Infections - Molds
Aspergillosis
• Ubiquitous mold transmitted by airborne conidia.
• It grows as septated hyphae branching at acute angles occasionally with
spore-producing fruiting bodies.
• It causes allergy (allergic bronchopulmonary aspergillosis) in healthy
individuals and severe sinusitis, pneumonia, and invasive disease in
immunocompromised hosts.
• Neutrophils and macrophages are the major host defenses, killing by
phagocytosis and reactive oxygen species.
• Macrophages recognize Aspergillus through TLR2 and Dectin-1. Neutropenia
is a major risk factor.
• Preexisting pulmonary lesions caused by tuberculosis, bronchiectasis, old
infarcts, or abscesses can develop secondary Aspergillus colonization
(aspergillomas) without tissue invasion.

Aspergillosis
– Adhesion to albumin, surfactant, and a variety of ECM proteins.
– Antioxidant defenses, including melanin pigment, mannitol, catalases & superoxide
dismutase.
– Phospholipases, proteases, and toxins, including aflatoxin (synthesized by fungus growing
on peanuts), a cause of liver cancer in Africa.
• Invasive aspergillosis in immunosuppressed hosts usually presents as
necrotizing pneumonia (forming “target lesions”) but often develops
widespread hematogenous dissemination.
• Aspergillus tends to invade blood vessels with resulting thrombosis;
consequently, areas of hemorrhage and infarction are superimposed on
necrotizing inflammation.

Zygomycosis (Mucormycosis)
• opportunistic infection in neutropenic patients and diabetics.
– Mucor, Absidia, Rhizopus, and Cunninghamella
• Non-septated fungi with right-angle branching.
• The primary site of infection (nasal sinuses, lungs, or GI tract) depends on
whether the spores are inhaled or ingested.
• Macrophages recognize Mucor via TLR2, yielding a proinflammatory cascade of
IL-6 and tumor necrosis factor (TNF)
• Neutrophils can kill hyphae after germination.
• Increased free iron increases Mucor growth.
• Diabetes increases the probability of infection by increasing the availability of
free iron through ketoacidosis.
• In diabetics, fungus may spread from nasal sinuses to the orbit or brain.
• These fungi commonly invade arterial walls and cause necrosis.

Meningeal blood vessels with angioinvasive Mucor species.
Note the irregular width and near right-angle branching of
the hyphae.

Parasitic Infections - Protozoa
Malaria
• Plasmodium falciparum causes severe malaria
• Plasmodium vivax, ovale, and malariae species cause less severe disease.
• From the mosquito salivary gland, sporozoites in the bloodstream invade
via the hepatocyte receptor for thrombospondin and properdin.
• Parasites multiply rapidly causing hepatocyte rupture & release of
merozoites (asexual, haploid).
• Merozoites bind to sialic acid residues on erythrocyt glycophorin and are
internalized.
• In erythrocytes, parasites hydrolyze red blood cell hemoglobin to generate
characteristic hemozoin pigment and undergo development.
• Trophozoites (single chromatin mass) divide to form schizonts (multiple
chromatin masses) that form new merozoites.
• Merozoites released by red cell lysis cause another round of erythrocyte
infection.
• A small fraction of the parasites within red blood cells develop into sexual
forms (gametocytes) that infect mosquitoes when they feed.

Malaria
• Infected erythrocytes to clump together or adhere to small vessel
endothelium (via “knobs” on erythrocyte surfaces that bind to endothelial
cells), causing vascular occlusion  ischemia  cerebral malaria.
• Induce high levels of cytokines, such as TNF and interferon-γ that suppress
red cell production, cause fever, and stimulate nitric oxide production by
release of glycosylphosphatidylinositol (GPI)-linked proteins (including
merozoite surface antigens) from infected erythrocytes.
• Use antigenic variation to continuously modify surface proteins.

Malaria
Resistance to Plasmodium occurs through the following:
• Heritable erythrocyte traits (common in areas of the world
where malaria is endemic):
– Sickle cell trait (HbS), hemoglobin C (HbC), loss of
globin genes (α- or β-thalassemia) and erythrocyte
glucose-6-phosphatase deficiency all lessen malaria
severity by reducing parasite proliferation and increasing
erythrocyte clearance by macrophages.
– Absence of Duffy blood group antigen prevents
Plasmodium vivax binding to erythrocytes.
• Antibody and T cell–mediated repertoires that develop after
chronic infection.

Babesiosis
• caused by malaria-like protozoans
transmitted from white-footed
mice to humans by Ixodes ticks.
• Babesia cause fever and, through
erythrocyte parasitization,
hemolytic anemia.
• • Babesia resemble malaria
schizonts but lack hemozoin
pigment, are more pleomorphic,
and form characteristic tetrads.
Erythrocytes with Babesia, including the
distinctive Maltese cross form.

Leishmaniasis
• Chronic inflammatory disease of skin, mucous membranes, and viscera
caused by Leishmania species, obligate intracellular parasites transmitted
by sandfly bites.
• The life cycle involves two forms:
– Promastigotes develop and live extracellularly in the sandfly vector.
– Amastigotes multiply intracellularly in the macrophages of mammalian
hosts.
• When sandflies bite infected hosts, infected macrophages are ingested;
amastigotes differentiate into promastigotes in the insect digestive tract
and migrate to the salivary gland.
• Subsequent bite of a second host delivers the promastigotes; these are
phagocytized by macrophages and undergo transformation in
phagolysosomes into amastigotes that then proliferate.

Leishmaniasis
• Disease manifestations vary with the species and host responses.
• A patient developing cutaneous disease or mucocutaneous disease, or visceral
disease depends on which organism is in play.
– Lipophosphoglycan on promastigotes
• activates complement  C3b deposition on the parasite surface and
increasing phagocytosis
• inhibits complement action (by preventing membrane attack complex
assembly).
– gp63 on promastigotes
• binds fibronectin to promote promastigote adhesion to macrophages
• cleaves complement and lysosomal antimicrobial enzymes to frustrate
killing.
– A proton pump in amastigotes reduces macrophage phagolysosome
acidity.

Trypanosomiasis
• caused by extracellular parasites
transmitted by tse tse flies
• disease of intermittent
fevers,lymphadenopathy,
progressive brain dysfunction
(sleeping sickness), cachexia &
death.
• Lymph nodes and spleen enlarge
as a result of hyperplasia &
infiltration by lymphocytes,
plasma cells, and parasite-laden
macrophages.
• When parasites breach the blood-brain barrier, they induce a
leptomeningitis and a demyelinating panencephalitis.

Giemsa stain of a tissue macrophage with Leishmania donovani

Parasitic Infections - Metazoa
Strongyloidiasis
• Larvae from soil directly penetrate the skin of humans  to lungs trachea
& are swallowed.
• Adult female worms produce eggs asexually in the mucosa of the small
intestine; passed larvae contaminate soil to complete the cycle.
• Diarrhea & malabsorption in immunocompetent hosts.
• larvae are present in the duodenal crypts with an underlying eosinophil-rich
infiltrate.
• Invade colonic mucosa & reinitiate infection in immunocompetent hosts.
• Such uncontrolled autoinfection results in massive larval burdens with
widespread invasion—occasionally complicated by sepsis caused by bacteria
carried into the bloodstream by parasites.

Tapeworms (Cestodes): Cysticercosis
• caused by larval development after the ingestion of eggs
• Taenia solium causes cysticercosis.
• transmitted to humans in two ways with distinct outcomes:
– Larval cysts (cysticerci) ingested in pork attach to the intestinal wall
where they mature and produce egg-laden proglottids (segments) that
are passed in stool.
– If intermediate hosts (pigs or humans) ingest eggs in feces
contaminated food or water, hatching larvae penetrate the gut wall, and
disseminate to encyst in many organs, including the brain (causing
severe neurologic manifestations).

Tapeworms (Cestodes): Hydatid disease
• caused by ingestion of Echinococcus granulosus eggs in food contaminated
with dog or fox feces.
• Eggs hatch in the duodenum and invade the liver, lungs, or bones, where
they form cysts.
• Humans are accidental hosts for E. granulosus and E.multilocularis; these
are normally passed only between the definitive (dog or fox) and
intermediate (sheep and rodents) hosts.

Schistosomiasis
• Caused by
– Schistosoma mansoni (Latin America, Africa, and the Middle East)
– Schistosoma haematobium (Africa)
– Schistosoma japonicum/Schistosoma mekongi (East Asia)
• Larvae penetrate human skin, migrate through the vasculature &
settle in the pelvic (S. haematobium) or portal (all others) venous
systems.
• Females produce eggs that may disseminate and are shed in urine or
stool.
• Eosinophil-rich granuloma formation & fibrosis.
• Urinary schistosmiasis is associated with urinary bladder squamous
cell carcinoma.

Lymphatic Filariasis
• caused by two nematodes :
– Wuchereria bancrofti (90% of cases)
– Brugia malayi
• Larvae are contracted from infected mosquitoes.
• Larvae develop into adults in lymphatic channels; those mate &
release microfilariae that enter the bloodstream and can then infect
secondary mosquitoes.
• Damage to lymphatics is mediated by TH1-mediated inflammation.
• Recurrent lymphadenitis.
• Chronic lymphadenitis with swelling of the dependent limb or
scrotum (elephantiasis).
• Tropical pulmonary eosinophilia.

Agents of Bioterrorism
• These pathogens pose the greatest danger due to efficient
disease transmission, significant morbidity and mortality,
relative ease of production and distribution, difficulty in
defending against or the ability to provoke alarm and fear in
the general public.

Agents of Bioterrorism
• Category A agents pose the greatest risk; readily
disseminated and/or transmitted from person to person, can
cause high mortality, and are likely to be societally disruptive.
– Smallpox
• Category B agents are relatively easy to disseminate (often
they are foodborne or waterborne) but have lower morbidity
& mortality.
– Brucella, Vibrio cholerae, and ricin toxins.
• Category C agents include emerging pathogens that have the
potential for being engineered for mass dissemination, with high
morbidity and mortality.
– Hantavirus and Nipah virus.

Infectious diseases

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