MYCOBACTERIUM TUBERCULOSIS

• Obligate human pathogen.
• Approximately 1/3 of the world population is infected, and there are 8-10 million new cases each year.
  – Of these, 5-10% will develop tuberculosis disease, which kills 1-4 million people annually.
• Individuals with HIV or other immune deficiencies are more likely to develop severe infection; because of this, co-infection with HIV and tuberculosis is a major public health concern in areas where both infections are endemic.
• Transmitted from human to human via respiratory aerosols
• Microbes are inhaled and travel to the lungs, where they are engulfed by alveolar phagocytes.
• Mycobacterium tuberculosis has evolved to highjack the innate immune response and to delay the adaptive immune response.
  – Disease development is the outcome of host and bacterial interactions that produces chronic inflammation.

Primary infection

• Occurs when a new host first encounters Mycobacterium tuberculosis
• Alveolar macrophages engulf Mycobacterium tuberculosisbacteria and sequesters the bacteria within a vacuole.
  – Recall that part of the innate immune response involves phagocytosis of microbes, followed by phago-lysosome fusion to expose the microbes to bactericidal lysozymes.
• Mycobacterium tuberculosis prevents phago-lysosome fusion,thus evading destructive enzymes.
  – Allows fusion with nutrient-filled vesicle to facilitates its own replication within the macrophage.
• Infected macrophage responds by secreting IL-12 and Tumor Necrosis Factor alpha (TNF-alpha).
• These cytokines recruit other immune cells to the area:
  – Natural killer cells, CD4+ T cells, and Monocytes.
• The CD4+ T cells differentiate to become Helper T cells that release Interferon gamma, which is a cytokine that activates macrophages.
  – Interferon gamma triggers the following antibacterial effects: Phagolysosome maturation, production of oxygen reactive species and nitric oxide, antimicrobial defensin recruitment, autophagy, and macrophage differentiation to form epithelioid cells.
  – Not surprisingly, patients with low production of TNF-alpha and/or interferon-gamma are more susceptible to severe Mycobacterium tuberculosis infection.
• Macrophage activation and the other effects of interferon-gamma promotes intracellular killing.
• Mycobacterium tuberculosis can induce macrophage apoptosis to escape killing.
• The monocytes recruited by IL-12 and TNF can also be infected; thus, instead of fighting bacterial spread, the newly arrived monocytes promote its success.
• The host’s response to Primary infection leads to chronic inflammation and granuloma formation.

Chronic inflammation produces granulomas, aka, tubercles

• Granulomas are hallmarks of primary tuberculosis infection that reflect interactions between the adaptive immune response and invading bacteria.
• They comprise aggregations of immune cells that wall-off bacteria in areas of the lungs and lymph nodes.
  – Necrotic center comprises apoptotic macrophages and Mycobacterium tuberculosis.
  – Center is surrounded by layers of epithelioid macrophages and Langhans giant cells (fused epithelioid cells).
  – B-cells, T-cells, and neutrophils also surround the necrotic center.
  – Outer fibrous layer encircles the granuloma.
• In a histological sample of infected lung tissue, we can see multiple granulomas with caseous (“cheese-like”) necrotic centers. Compare these areas with the remaining alveolar tissue, and consider how granulomas interfere with gas exchange in the lungs.
• Primary tuberculosis infection is typically characterized by lesions in the lower lobes of the lung (Ghon foci) and in the hilar lymph nodes, which drain the lungs.
  – Collectively, the pulmonary and lymph node lesions are referred to as the Ghon complex.
• The Ghon complex can calcify and become a fibrotic Ranke complex, which reflects latent infection.
  – Early studies stressed the benefits of granuloma formation to the host – bacterial spread is prevented by layers of host tissues. However, we now recognize that those layers of cells also prevent the host immune system or clinical therapies from reaching the bacteria, which allows infection to persist in a dormant state.
  – Ultimately, the dormant bacteria can reactivate to cause secondary infection.

Secondary infection

• Tuberculosis infection in an individual who has previously been exposed to Mycobacterium tuberculosis
• Occurs upon reactivation of dormant bacteria or re-infectionfrom a new source.
• Secondary infection is characterized by lesions in the upper lobes of the lungs and does not involve the lymph nodes (in contrast to primary infection lesions).
• Many lesions heal spontaneously, and can leave behind fibrotic scars.
• Others lead to caseation and cavitation.
  – Bacteria replicate within the lesions and are released in sputum along with fragments of necrotic lung tissue.
  – The contaminated sputum constitutes the is the primary route of Mycobacterium tuberculosis transmission between humans.

Hematogenous spread of Mycobacterium tuberculosis

• Occurs in primary or secondary pulmonary infections.
• It is especially likely in individuals with impaired cellular immunity.
• Miliary tuberculosis occurs when the resulting lesions are very tiny (like millet seeds); infection can by systematic or localized within a specific organ.
• Isolated tuberculosis with larger lesions can also occur.
• Extrapulmonary infections can occur in any organ, but are particularly common in the liver, spleen, kidney, adrenal glands, bone marrow, lymph nodes, and the meninges.

Prevention and treatment

• Bacille Calmette-Guerin (BCG) vaccine is administered to children in areas where tuberculosis is endemic.
  – Vaccine is made with attenuated Mycobacterium bovis.
  – Significant limitations: it is only effective against some forms of childhood tuberculosis, and is not effective against pulmonary tuberculosis, which is the most prevalent form of the disease.
• Skin and blood tests can determine if Mycobacterium tuberculosis is present in the body.
  – These tests do not distinguish between latent and active infections; individuals who’ve had the Mycobacterium bovis vaccine will test positive.
• Chest x-rays can show cavitation and pulmonary tissue damage.
• Mycobacterium tuberculosis is resistant to antibiotics
  – Long-term, multi-drug therapy is necessary.
  – “Extensively drug-resistant” strains (XDR TB) are on the rise in some regions.

Characteristics:

• Acid-fast
• Not grown in vitro; in the lab, it’s often grown in mouse footpads.
• 14-day doubling time
• Human pathogen
  — Has also been found in armadillos and some other non-human primates.
• Route of transmission is not entirely established
  — Long-term contact is necessary.
  — It is thought that respiratory, and possibly skin secretions,transmit the bacteria.
• Prefers cooler temperatures
  — Tends to infect superficial structures such as the skin and peripheral nerves
  — In some individuals, the anterior eye chambers and nasal cavities are also affected.
• Long incubation period: typically between 3-10 years.
• Intracellular pathogen
  — Macrophages and the Schwann cells of peripheral nerves.
  — In the histology image, we see foamy macrophages infected with Mycobacterium leprae
  — Schwann cell invasion causes demyelination and reduced conduction.
  — In the histology image, we see an example of a cutaneous nerve invaded by Mycobacterium leprae.

HANSEN’S DISEASE

• Chronic, typically non-fatal disease.
• Major cause of peripheral neuropathy in areas where infection is endemic.
• Treatment can include administration of dapsone, rifampicin, and clofazimine.
• Be aware that Mycobacterium lepromatosis is also associated with Hansen’s disease; it causes diffuse lepromatous leprosy, and is endemic in Mexico and Costa Rica.

Infection produces a range of clinical manifestations

• Disease severity is determined by the host’s cellular immune response, which is influenced by genetic components and environmental conditions.
• Tuberculoid leprosy is the milder, less infectious form; Lepromatous leprosy is the more severe, disseminated, and infectious form; Borderline leprosy is in the middle, and is characterized as “immunologically unstable.”
• Individuals move along this spectrum according to shifts in their immune system responses.

Be aware that there are additional clinically recognized stages that we have omitted for simplicity.

Tuberculoid leprosy

• Associated with CD4+ T cell activation and type 1 cytokines, particularly IL-2 and interferon-gamma.
  — This produces an effective immune response that restricts infection.
  — Low bacillary load = Paucibacillary Hansen’s disease.
  — Negative slit-skin smear test
• Tuberculoid leprosy is characterized by 5 or fewer lesions with granulomatous inflammation
  — Over time, inflammation damages the peripheral nerves.
  — Lesions are dry and scaly with irregular edges; the center of the lesions is typically hypo-pigmented.
• Ultimately, nerve damage results in the loss of sensation; hair loss and reduced sweating ability can also occur.

Lepromatous leprosy

• Associated with CD8+ T cells and type 2 cytokines, particularly IL-4 and IL-10.
• This response produces an ineffective cellular immune response that facilitates disseminated infection.
• High bacillary load = Multibacillary Hansen’s disease
• Positive slit-skin test
• Antibodies may be produced, but they form immune complexes that compound tissue damage.
• Widespread lesions with thickened skin and nerve damage occurs.
  — Facies leonina, aka, lion face, is the result of thickened skin around the ears, nose, and brows with loss of the eyebrows and eyelashes.
  — Major nerves are commonly affected, including the median and ulnar nerves of the upper extremity, and the common fibular nerve and posterior tibial nerves of the lower extremity. The facial nerve is also often damaged.
  — Nerve damage can lead to muscular atrophy and paralysis.
  — Additionally, some patients experience testicular damage.

Leprosy reactions

• Immune reactions with acute inflammation that can cause permanent nerve damage, so they need to be treated right away.
• Analgesics can help with pain, and corticosteroids are necessary to suppress the immune system if nerve damage is suspected.

Type 1 Reactions

• Associated with tuberculoid and lepromatous leprosy
• Reversal reactions are caused by delayed hypersensitivityimmune responses
• Edema and inflammation
• Damage to the peripheral nerve trunks is a major concern.

Type 2 Reactions

• Associated with lepromatous leprosy
• Characterized by erythema nodosum leprosum that presents as subcutaneous nodules of inflammation on the extensor surfaces of the extremities.
• Brought on by humoral immune responses that result in immune complex deposition.
• Vasculitis and other complications that damage nerves and organs.
• In patients where corticosteroids are contraindicated, thalidomide can be administered; however, this drug is associated with severe birth defects, so caution is warranted in women of child-bearing age.

General characteristics of Mycobacteria:

• They have lipid-rich cell walls that are:
  — Acid-fast
  — Resistant to detergents and antibiotics
  — Contain antigens that stimulate the host immune response.
  — Layers:

1. Cytoplasmic membrane
2. Peptidoglycan layer – tends to stain weakly Gram-positive
3. Arabinogalactan layer is a branched polysaccharide macromolecule that comprises arabinose and galactose residues; it links to the peptidoglycan layer, below.
4. Mycolic acids, which comprises long-chain fatty acids; these acids contribute to the low permeability of Mycobacteria cell walls.

Be aware that some authors describe an outer capsule or capsule-like material.

• Non-motile, non-spore-forming, aerobic, have high amounts of Guanine and Cytosine in their DNA, slow-growing, and most are weakly Gram-positive

MYCOBACTERIUM TUBERCULOSIS

• Primary cause of tuberculosis
• 18-hour doubling time
• Produces non-pigmented colonies
  — We see this in the image of Mycobacterium tuberculosisgrown on Lowenstein-Jensen agar.
• Cord factor (aka, trehalose dimycolate) is a lipid component of the cell wall that contains mycolic acids and gives virulent strains of Mycobacterium tuberculosis a “serpentine cord”arrangement.
• Obligate human pathogens,
• Humans are its only reservoir.
• Transmitted in respiratory droplets, especially sputum produced by individuals with severe secondary pulmonary infections.
• HIV-positive individuals and those with other cellular immunodeficiencies, including organ transplant recipients, are more susceptible to serious infection.
• Intracellular pathogen
• Virulence factors promote bacterial survival and replication in host cells:
  — Secretion systems and adhesins facilitate host cell invasion
  — Inhibition of phagosome-lysosome fusion allows the bacteria to avoid degradative lysosomal enzymes
  — Resistance to reactive oxygen species and nitric oxide, which are otherwise bactericidal
  — Prevention of cellular apoptosis, which allows the bacteria to replicate intracellularly; it is thought that, when the host cell is no longer useful, the bacteria promote necrosis, which facilitates their spread to new tissues and/or new hosts.
  — In summary, these virulence factors promote long-term survival of the pathogen; thus, tuberculosis is a disease of chronic inflammation.
• Treatment for tuberculosis is complex, and involves long-term use of multiple antibiotics.
• Detection:
  — Microscopy is a fast way to identify Mycobacteria by their acid-fast cell walls
  — Nucleic acid-based tests are then used to determine the specific species of Mycobacterium
  — Cultures taken from respiratory secretions can also be useful; however, remember that Mycobacteria have slow growth rates.
  — Molecular probes and mass spectrometry can be used to identify Mycobacteria.

Infection sites
Hematogenous or lymphatic spread of Mycobacterium tuberculosis can lead to disseminated infections or localized infections in specific organs. When the lesions are very tiny, this is called “Miliary tuberculosis.”

Pulmonary tuberculosis

• The most common site of infection.
• Characterized by granulomas and scarring; secondary infections can produce caseation and cavitation.
• Symptoms include fever, night sweats, chest pain, coughing up blood, fatigue, and weight loss.
• Pulmonary tuberculosis is often accompanied by infection of nearby lymph nodes.

Lymph nodes

• Most commonly nodes in the cervical region
  — “Scrofula”
• Infected nodes tend to be non-tender, firm, and discrete.
• As infection progresses, nodes may form a mass of nodules.

Renal tuberculosis

• Associated with renal transplants
• Accounts for approximately 30% of extrapulmonary tuberculosis.
• Patients often have sterile pyuria (elevated white blood cell count without evidence of bacterial growth) and microscopic hematuria.
• Be aware that tuberculosis can spread through the urinary tract and to the genital tract.

Tuberculous osteomyelitis/arthritis

• Most commonly effects the thoracic vertebrae, especially in children and young adults.
• Spinal tuberculosis, aka, Pott’s disease, often produces Kyphosis or other deformities.

Gastrointestinal tuberculosis

• Most often occurs after ingestion of contaminated milk or swallowed respiratory tract mucus.
• Infection can involve the gastrointestinal tract, often where the ileum and cecum meet, as well as the peritoneum and abdominal lymph nodes.
• Ulcerative lesions are common.

Erythema nodosum

• Characterized by subcutaneous nodules on the anterior surface of the lower extremities.

Tuberculous meningitis

• Most lethal form of infection.
• Tends to affect young children and HIV-positive adults.
• Associated with hyponatremia (low blood sodium concentration).

ADDITIONAL SPECIES ASSOCIATED WITH TUBERCULOSIS

Mycobacterium bovis

• Associated with cattle
• Zoonotic infection when contaminated meat or unpasteurized milk is consumed.
• Mycobacterium bovis bacillus Calmette-Guerin (BCG) is a derivation of Mycobacterium bovis
  — Used in a childhood vaccine to prevent some forms of tuberculosis infection.

Mycobacterium africanum

• Tuberculosis-causing strain endemic to West Africa.

General Characteristics

• Small, Gram-negative rods.
• Visualized with Giemsa staining.
• Lipo-polysaccharides in their membranes.
  – Weak endotoxin activity.
• Specific Major Outer Membrane Proteins (MOMPS) that allow us to identify discrete serovars.
• They are “energy parasites”
  – They rely on host cellular ATP.
• Tropism:
  – Chlamydiaceae can enter non-ciliated columnar, cuboidal, and transitional epithelial cells.
  – Line the upper female reproductive tract, the urethra, the conjunctiva, and parts of the respiratory tract.
  – Thus, these are the sites of infection.

Unique developmental cycle
– Differentiate from elementary bodies, which are metabolically inactive infectious forms, to reticulate bodies,which are metabolically active noninfectious forms.

We show how this development cycle facilitates infection and destruction within host cells.

• An infectious elementary body is ingested by the cell and contained within a phagosome.
• Within the phagosome, the elementary body transforms to become a metabolically active reticulate body.
• The reticulate body replicates via binary fission; the daughter cells reorganize into elementary bodies.
• The phagosome containing both reticulate and elementary bodies is called an “inclusion body”
  – We can see examples of inclusion bodies in the histologic sample.
• Within a couple of days, the host cell bursts, which releases elementary bodies that can then go on to infect new host cells.

Chlamydia trachomatis

• Responsible for a range of infections.
• Characterized by mucopurulent discharge characterizes these infections.
• Treat with azithromycin, doxycycline, or erythromycin.

• Trachoma is a chronic infection caused by Serovars A, B, and C
  – Transmitted via clothing, hands, and flies that move from person-person.
  – Infection leads to follicular conjunctivitis; scarring turns the eyelids and lashes inward.
  – Over time, the resulting abrasions can cause corneal scarring and pannus, leading to blindness.
  – Trachoma is endemic in areas of sub-Saharan Africa, the Middle East, and South Asia.
  – Children are predominantly affected.

• Urogenital Infections are caused by Serovars D-K
  – The number one cause of sexually-transmitted urogenital infections in the United States.
  – Many women are asymptomatic, and, therefore, are key reservoirs; other women experience urethritis and/or inflammation of the reproductive tract (pelvic inflammatory disease, endometritis, etc.)
  – Most men are symptomatic and experience urethritis.
  – Co-infection with Neisseria gonorrheae is common.
  – Indicate that infection can provoke reactive arthritis, aka, Reiter syndrome, which is an autoimmune response characterized by arthritis, urethritis, conjunctivitis, and muco-cutaneous lesions.
  – Vertical transmission of Chlamydia trachomatis can lead to neonatal conjunctivitis or infant pneumonia; treatment of pregnant mothers can prevent transmission.

• Inclusion conjunctivitis is an acute follicular conjunctivitis that can become chronic with scarring.
  – It is associated with urogenital infections.

• Lymphogranuloma venereum is associated with Serovars L1, L2, and L3
  – This sexually transmitted infection is endemic in tropical and subtropical areas; sporadic outbreaks have been reported elsewhere.
  – The early stage is characterized by a localized lesion at the site of infection (typically the genitals or rectum); the lesion is painless, and heals spontaneously.
  – However, as infection moves to the lymph nodes, buboesform; show that they typically appear in the inguinal or femoral regions. Buboes can progress to fistulas that drain and/or rupture, and genital elephantitis can develop. Proctitis can also occur (inflammation of the anus and lining of the rectum).
  – Systemic symptoms of lymphogranuloma venereum include fever, chills, headache, and muscle and joint pains.

Chlamydophila pneumoniae

• Causes mild to severe respiratory infections.
  – Atypical pneumonia may require hospitalization.
  – Macrolide administration is usually effective.

Chlamydophila psittaci

• Associated with birds; thus, it is said to cause “Parrot fever.”
• Infections can range from asymptomatic to severe, with pulmonary, hepatic, splenic, and other organ involvement.
• Though rare, infection can lead to organ necrosis and hemorrhage, as well as airway obstruction.
• Treatment includes doxycycline or macrolides.

• Small, intracellular pathogens
• Obligate aerobes
• Gram-negative rods that stain best with Giemsa or Gimenez stains.
• Some infections caused by these species are self-limiting
  • Doxycycline can be administered to shorten illness duration and prevent complications.

Species overview

Be aware that all of these species were formerly categorized as members of Rickettsiaceae, and that intertextual variation exists.

Rickettsiaceae damages endothelial cells of blood vessels

• Rickettsia rickettsii causes Rocky Mountain Spotted Fever
• Rickettsia akari causes rickettsial pox
• Rickettsia prowazekii and Rickettsia typhi cause different forms of typhus
• Orientia tsutsugamushi causes scrub typhus.
  to damage to the endothelial cells of blood vessels.

Anaplasmataceae

• Ehrlichia chaffeensis causes human monocytic ehrlichiosis
• Ehrlichia ewingii causes human ewingii ehrlichiosis
• Anaplasma phagocytophilum causes human granulocytic anaplasmosis.

Coxiellaceae

• Coxiella burnetti causes Q fever.

INFECTIONS, RESERVOIRS, AND VECTORS

Rickettsia rickettsii

• Rocky Mountain Spotted Fever
  — Fever, headache, myalgias, and, sometimes, confusion (as a result of CNS involvement).
  — Patients commonly develop a macular rash that can progress to petechiae; the rash characteristically begins on the wrists and ankles, then spreads to the palms, soles, and trunk. This pattern of spread is a helpful distinguisher.
  — Gastrointestinal involvement is possible, and can cause abdominal pain, nausea, vomiting, and/or diarrhea.
  — Left untreated, disseminated vasculitis can lead to multi-organ failure.
• Ticks and rodents are key reservoirs; hard ticks are vectors.

Rickettsia akari

• Rickettsialpox
  — Typically less severe than Rocky Mountain Spotted Fever.
  — Patients experience fever and papulovesicular rash with eschars. Headaches and myalgia are possible.
  — Rodents are the reservoirs; mites are the vectors.

Rickettsia prowazekii

• Epidemic typhus
  — Brill-Zinsser disease is the result of latent infection that manifests years, even decades, later.
  — Patients experience fever, headache, chills, myalgia, and a macular rash that spreads from the trunk to the extremities.
  — CNS involvement is possible, and can present as confusion.
  — If left untreated, vasculitis can lead to multi-organ failure.
  — Humans are the main reservoir, and the human body louse is the vector; be aware that flying squirrels and their fleas have also been described as reservoirs and vectors.

Rickettsii typhi

• Endemic typhus (aka, murine, typhus)
  — Patients experience fever, headache, myalgia, and a maculopapular rash that spreads from the trunk to the extremities.
  — Gastrointestinal involvement is possible, and more common in children.
  — Cases are typically mild, but severe cases can lead to renal dysfunction or respiratory impairment (experienced as cough, dyspnea).
  — Small mammals, particularly cats and rodents, are key reservoirs; their fleas are the vectors.

Orientia tsutsugamushi

• Scrub fever
  — Fever, intense headahces, mylagias, and a maculopapular rash that starts on the trunk; in some cases, eschars will form, especially at the site of inoculation.
  — Lymphadenopathy and pulmonary and neurologic involvement are common; gastrointestinal involvement may also occur.
  — Reservoirs include mites (chiggers) and rodents; mites are the vector.

Ehrlichia chaffeensis

• Human monocytic ehrlichiosis
  — Fever, headache, and myalgia; Coughing is common in adults.
  — The rash associated with this infection varies, and is more common in children.
  — Central nervous system involvement is possible.
  — Leukopenia, thrombocytopenia, and elevated transanimases.
  — Deer, dogs, and other mammals are common reservoirs; soft ticks are the vector.

Anaplasma phagocytophilum

• Granulocytic anaplasmosis
  — Similar symptoms and signs to human monocytic ehrlichiosis
  — Rash is rare.
  — Small mammals are the reservoirs; soft ticks are the vector.

Coxiella burnettii

• Q fever
  — Fever, headache, and myalgia, but no rash.
  — Chronic Q fever can lead to serious complications, including hepatitis, pneumonia, and subacute endocarditis.
  — Reservoirs include mammals, ticks, and birds; though ticks are a potential vector, most cases of Q fever are the result of the aerosol inhalation or consumption of the bacteria in contaminated milk.

• Zoonotic illnesses, and most are transmitted via arthropod vectors.

Details and less common species can be found in separate tutorials.

Rash, Fever, & Headache

Rickettsia species:

• Intracellular rods responsible for a range of illnesses.
• Primarily target the lining of small vessels.

Pathologies:

• Rocky Mountain Spotted Fever
  – Bacteria are transmitted by hard ticks.
  – Infection produces a rash that begins on the hands and feet, then spreads to the trunk
  – Ocular involvement, such as conjunctivitis, is common.
  – Without treatment, widespread vascular damage can lead to organ failure and death.

• Rickettsialpox
  – Bacteria that cause rickettsialpox are transmitted by mites.
  – Infection is characterized by an eschar, which is an area of redness with a blackish scab, at the site of the mite bite, and a vesiculopapular rash. The rash somewhat resembles the rash of chicken pox, which is why this illness is called “rickettsialpox”.
  – Infection is usually mild and self-limiting.

• Epidemic typhus
  – Bacteria are transmitted via the human body louse.
  – Infection produces a pinkish macular rash that begin on the trunk and spreads to the extremities, and that the palms and soles are spared.
  Notice that this rash pattern is exactly the opposite that of Rocky Mountain Spotted Fever, which begins on the hands and feet and spreads to the trunk.
  – Widespread vascular damage can lead to death.
• Brill-Zinsser disease occurs when latent infection re-emerges; it is typically less severe than the initial infection, and rash may be absent.

• Endemic typhus, aka, Murine typhus
  – Bacteria are transmitted by fleas that parasitize small mammals, including cats.
  – Infection is similar to epidemic typhus, though usually milder.

Borrelia burgdorferi

• Spirochete transmitted by hard ticks.
• Causes Lyme Disease in the United States.
  – Other species of Borrelia are responsible for Lyme Disease outside the United States.
• Lyme disease is a multi-system inflammatory disease.
  – Early stages are often, but not always, characterized by localized erythema migrans – which often looks like a “bulls eye”.
  Some patients also experience flu-like symptoms such as fever and headache.
  – Later, infection can produce multiple, but usually smaller, areas of erythema migrans.
  Bacteria can spread to multiple organ systems, notably, the nervous system, heart, and musculoskeletal structures.

Fever & Headache

Coxiella burnetti

• Intracellular rods.
• Not transmitted via arthropod vectors
• Bacterial endospores are inhaled from animal hides or wastes.
• Not everyone who inhales the endospores will get sick.
  – Some patients will develop Q fever, which presents with mild to severe flu-like symptoms.
  Severe cases can lead to pneumonia.
  Some patients develop hepatitis; Q fever hepatitis has a characteristic histopathology with fibrin ring granulomas that may or may not have fat vacuoles inside.
  – Chronic Q fever may develop later; endocarditis is a common complication.

Borrelia recurrentis and other Borrelia species

• Species of Borrelia that cause relapsing fever are transmitted via body lice and soft ticks.
• As its name suggests, relapsing fever is characterized by recurrent episodes of fever and septicemia, which are the result of bacterial proliferation.
  – Borrelia membrane proteins undergo antigenic variation, which promotes cycling between bacteremia and clearance.
• We illustrate this cycle, as follows:
  – In response to bacteremia, host antibodies form and begin to clear the bacteria from the blood.
  – Bacteremia recedes, and the host enters the afebrile stage.
  – However, the bacteria rapidly undergo antigenic variation.
  – The new variants evade host antibodies and proliferate in the host.
  – Thus, the host enters a new febrile episode.
• Symptoms of relapsing fever can range from mild to severe, and, in large part, depends on the causative species.
  – In addition to fever and headache, indicate that mild cases tend to produce muscle and joint pain, abdominal tenderness, and vomiting. Patients may also have jaundice and low platelet counts.
  – Severe cases can affect major organ systems and hepatic or cardiac failure or cerebral hemorrhaging.

• Gastric helicobacter because it colonizes the stomach
• Transmission is human to human; exact mechanisms uncertain.
• Life-long colonization; infection typically occurs during childhood and produces symptoms during adulthood.
• Gatalase, oxidase, and urease positive;
• Spiral, Gram-negative rods that can appear as coccoid in older cultures.
• Microaerobic: Grow in conditions of reduced oxygen and increased carbon dioxide.

Virulence factors

• Helicobacter pylori has several adaptations that allow it to survive the acidic environment of the human stomach and persist for decades.
• Urease converts urea to ammonia and bicarbonate to neutralize gastric acids.
• Multiple flagella provide corkscrew motility
• Mucinase production allows the bacteria migrate through the viscous mucus that covers the surface of the stomach.
• Infection triggers host production of IL-8, which is a pro-inflammatory cytokine that recruits neutrophils that release harmful molecules and damage host tissues.
• The bacteria protect themselves from these harmful molecules by producing superoxide dismutase and catalase, which detoxify reactive oxygen species.
• Lipopolysaccharide endotoxin; however, as compared with many other Gram-negative bacteria, its endotoxin has low toxicity.
• Vacuolating cytotoxin A promotes pore formation, disrupts cell signaling, and induces apoptosis and necrosis of host cells.
• Cytotoxin-associated gene A (cagA) product promotes proliferation and morphological changes in host tissues, and induces T-cell  apoptosis.
  – Type IV secretion systems* inject the cagA effector protein into host cells.

Infection

• Gastritis is inflammation of the stomach lining with infiltration of neutrophils and mononuclear cells; T-1 helper cells are also implicated.
  – Some individuals are asymptomatic, and others experience an acute phase of nausea, bloating, and vomiting.
  – Inflammation can be localized to one area, usually the pyloric antrum, or widespread
  – In a subset of patients, gastritis progresses to more serious conditions.

• Peptic ulcers
  – 10-20% of patients with gastritis will develop peptic ulcers, in which inflammation erodes the stomach tissues.
  – Ulcers can be located in the stomach, or they can be in the duodenum, which is the first portion of the small intestine.

• Gastric adenocarcinoma
  – In approximately 1-2%, chronic inflammation will lead to gastric adenocarcinoma.
  – This occurs when inflammation leads to metaplasia; over time, the gastric mucosa is replaced by fibrotic tissue, and can become neoplastic.
  – Reduced gastric acid secretion is associated with a higher risk of adenocarcinoma.

• Gastric-associated lymphoid tissue B-cell lymphomas
• In response to Helicobacter pylori infection, lymphoid tissues infiltrate the stomach; in some cases, monoclonal B cells proliferate and form MALT lymphomas (MALT = Mucosa-Associated Lymphoid Tissue).

Summary Illustration:

We draw the stomach, esophagus, and duodenum.

Gastritis can be localized in the pyloric antrum, and indicate that this is associated with increased acid production and formation of duodenal ulcers.

• Multifocal inflammation, as in pangastritis, is associated with atrophy and reduced acid production; this is associated with gastric metaplasia and cancer.
• Helicobacter pylori infection causes destruction of the mucosa, which allows acids and toxins, as well as the microbes themselves, access to deeper tissues.
• Ulceration leads to bleeding, perforation, and, in severe cases, metaplasia.

Treatment

Because chronic gastritis can lead to severe consequences, treatment is important.

• Macrolides, Beta-lactams, and proton-pump inhibitors.

Enterohepatic helicobacters

Helicobacter cinaedi and Helicobacter fenneliae

• Invade the intestines and liver, and can cause gastroenteritis and bacteremia, particularly in immunocompromised individuals.