Brucellosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]

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Overview

Brucella is usually transmitted via the digestive route to the human host. Following transmission, white blood cells phagocyte the pathogen and transports it via the hematologic or lymphatic route to different organs, specially to those of the reticuloendothelial system.

Pathophysiology

Brucellosis is a zoonotic disease, Humans could be infected by eating undercook meat or raw dairy products, inhalation of the bacteria, and direct contact of bacteria with skin wounds or mucous membranes. Following transmission, white blood cells phagocyte the pathogen and transports it via hematologic or lymphatic route to different organs, specially to those of the reticuloendothelial system. Endotoxic lipopolysaccharide LPS, plays an important role in survival of bacteria inside monocytic cell, supressing phagosome-lysosome fusion, and internalizing bacteria into endoplasmic reticulum. The pathophysiology of Brucellosis can be described in the following steps:[1][2][3][4][5][6][7][8][9][10][11][12][13]

Transmission

According to CDC, humans are generally infected with Brucellosis in one of the following three ways:[1][14]

Humans are generally infected with brucellosis in one of three ways

Eating undercooked meat or consuming unpasteurized/raw dairy products

  • The most common way to be infected is by eating or drinking unpasteurized/raw dairy products.
  • When sheep, goats, cows, or camels are infected, their milk becomes contaminated with the bacteria.
  • If the milk from infected animals is not pasteurized, the infection will be transmitted to people who consume the milk and/or cheese products.

Breathing in the bacteria that cause brucellosis (inhalation)

  • Breathing in the bacteria that causes brucellosis may also lead to infection.
  • This risk is generally greater for people in laboratories that work with the bacteria.
  • In addition, slaughterhouse and meat-packing employees have also been known to be exposed to the bacteria and ultimately become infected.

Bacteria entering the body through skin wounds or mucous membranes

  • Bacteria can also enter wounds in the skin/mucous membranes through contact with infected animals.
  • This poses a problem for workers who have close contact with animals or animal excretions (newborn animals, fetuses, and excretions that may result from birth). Such workers may include:
    • slaughterhouse workers
    • meat-packing plant employees
    • veterinarians

Other mode of transmission

  • Person-to-person spread of brucellosis is extremely rare.
  • Infected mothers who are breast-feeding may transmit the infection to their infants.
  • Sexual transmission has been rarely reported.
  • While uncommon, transmission may also occur via tissue transplantation or blood transfusions.

Incubation

Incubation period of Brucellosis varies from one to four weeks. But occasionally, it may be as long as several months. 

Dissemination

Following transmission, Brucellae is ingested by macrophages and polymorphonuclear cells. On ingestion, they replicate intracellularly inside the lysed cells and disseminate systemically. 

Seeding

  • On transmission, bacteria is actively phagocytosed by neurophilic granulocutes and monocytes.

Immune response

MAIN MECHANISM OF IMMUNE RESPONSE IS CELL MEDIATED IMMUNITY, pls mention this Brucellosis elicits both humoral and cell-mediated immune responses:[1][2][3][4][5][6][7][8][9][15][16]

Humoral immune response

Humoral response has a limited role in protecting host from Brucellae. On activation, B-cell produce IgM class antibody, which is followed by IgG antibodies . Antibodies promote clearance of extracellular bacteria and facilitate phagocytosis of the Brucellae.

Cell mediates immune response

Pathogenesis

The pathogenesis of brucellosis is complex and not fully understood:[1][2][3][4][5][6][7][8][9][17][18][19]

By avoiding innate immunity, brucella survive with in monocytic cells.

  • Endotoxic lipopolysaccharide (LPS), plays a key role in survival of bacteria inside monocytic cell.
  • LPS helps in survival of the bacteria inside the monocytic cell, by suppressing phagosomelysosome fusion, internalizing bacteria into endoplasmic reticulum and inhibiting apoptosis of infected cell.
  • Type IV secretion system (VirB) and type III secretion system, that regulates intracellular survival and trafficking has been identified, although type 3 not yet confirmed. Secretion system plays an important role in intracellular transport of the bacteria Acid-stable proteins produced by brucella, facilitates the survival in phagosomes
  • Cu-Zn superoxide dismutase, produced by brucellae, gives them resistance from reactive oxygen intermediates.
  • Two component BvrS/BvrR system, codes for histidine kinase sensor. Histidine kinase sensor plays an important role in controlling the expression of molecular determinants which are necessary for cell invasion.[20]
  • Hemolysins help the bacteria to be realeased from a cell and induce cell necrosis.

Genetics

There is no known genetic association to Brucellosis.

Associated factors

Microscopic Pathology

  • Brucella spp. are poorly staining, small gram-negative coccobacilli (0.5-0.7 x 0.6-1.5 µm).
  • Brucella spp. are seen mostly as single cells and appearing like “fine sand”.[22]
  • On microscopic histopathological analysis of the liver, common findings are:
    • Granulomas with centrilobular necrosis or focal necrosis and parenchyma destruction.[23]

Reference

  1. 1.0 1.1 1.2 1.3 Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). "Brucellosis". N Engl J Med. 352 (22): 2325–36. doi:10.1056/NEJMra050570. PMID 15930423.
  2. 2.0 2.1 2.2 "CDC".
  3. 3.0 3.1 3.2 Zhan Y, Liu Z, Cheers C (1996). "Tumor necrosis factor alpha and interleukin-12 contribute to resistance to the intracellular bacterium Brucella abortus by different mechanisms". Infect Immun. 64 (7): 2782–6. PMC 174139. PMID 8698508.
  4. 4.0 4.1 4.2 Larralde de Luna M, Raspa ML, Ibargoyen J (1992). "Oral-facial-digital type 1 syndrome of Papillon-Léage and Psaume". Pediatr Dermatol. 9 (1): 52–6. PMID 1574477.
  5. 5.0 5.1 5.2 Gazapo E, Gonzalez Lahoz J, Subiza JL, Baquero M, Gil J, de la Concha EG (1989). "Changes in IgM and IgG antibody concentrations in brucellosis over time: importance for diagnosis and follow-up". J Infect Dis. 159 (2): 219–25. PMID 2915152.
  6. 6.0 6.1 6.2 Arenas GN, Staskevich AS, Aballay A, Mayorga LS (2000). "Intracellular trafficking of Brucella abortus in J774 macrophages". Infect Immun. 68 (7): 4255–63. PMC 101738. PMID 10858243.
  7. 7.0 7.1 7.2 Boschiroli ML, Ouahrani-Bettache S, Foulongne V, Michaux-Charachon S, Bourg G, Allardet-Servent A; et al. (2002). "Type IV secretion and Brucella virulence". Vet Microbiol. 90 (1–4): 341–8. PMID 12414154.
  8. 8.0 8.1 8.2 Lapaque N, Moriyon I, Moreno E, Gorvel JP (2005). "Brucella lipopolysaccharide acts as a virulence factor". Curr Opin Microbiol. 8 (1): 60–6. doi:10.1016/j.mib.2004.12.003. PMID 15694858.
  9. 9.0 9.1 9.2 DelVecchio VG, Kapatral V, Elzer P, Patra G, Mujer CV (2002). "The genome of Brucella melitensis". Vet Microbiol. 90 (1–4): 587–92. PMID 12414174.
  10. Moreno E, Moriyon I (2002). "Brucella melitensis: a nasty bug with hidden credentials for virulence". Proc Natl Acad Sci U S A. 99 (1): 1–3. doi:10.1073/pnas.022622699. PMC 117501. PMID 11782541.
  11. Gorvel JP, Moreno E (2002). "Brucella intracellular life: from invasion to intracellular replication". Vet Microbiol. 90 (1–4): 281–97. PMID 12414149.
  12. Ko J, Splitter GA (2003). "Molecular host-pathogen interaction in brucellosis: current understanding and future approaches to vaccine development for mice and humans". Clin Microbiol Rev. 16 (1): 65–78. PMC 145300. PMID 12525425.
  13. Dornand J, Gross A, Lafont V, Liautard J, Oliaro J, Liautard JP (2002). "The innate immune response against Brucella in humans". Vet Microbiol. 90 (1–4): 383–94. PMID 12414158.
  14. [CDC "https://www.cdc.gov/brucellosis/transmission/index.html"] Check |url= value (help). External link in |title= (help)
  15. Khan M, Harms JS, Marim FM, Armon L, Hall CL, Liu YP; et al. (2016). "The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response" Check |url= value (help). Infect Immun. 84 (12): 3458–3470. doi:10.1128/IAI.00531-16. PMC 5116723. PMID 27672085.
  16. Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). "Brucellosis". N Engl J Med. 352 (22): 2325–36. doi:10.1056/NEJMra050570. PMID 15930423.
  17. Barquero-Calvo E, Chaves-Olarte E, Weiss DS, et al. Brucella abortus uses a stealthy strategy to avoid activation of the innate immune system during the onset of infection. PLoS One 2007; 2:e631.
  18. Gorvel JP, Moreno E. Brucella intracellular life: from invasion to intracellular replication. Vet Microbiol 2002; 90:281.
  19. Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). "Brucellosis". N Engl J Med. 352 (22): 2325–36. doi:10.1056/NEJMra050570. PMID 15930423.
  20. Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). "Brucellosis" Check |url= value (help). N Engl J Med. 352 (22): 2325–36. doi:10.1056/NEJMra050570. PMID 15930423.
  21. Moreno S, Ariza J, Espinosa FJ, Podzamczer D, Miró JM, Rivero A; et al. (1998). "Brucellosis in patients infected with the human immunodeficiency virus" Check |url= value (help). Eur J Clin Microbiol Infect Dis. 17 (5): 319–26. PMID 9721960.
  22. Brucellosis. Wikipedia. https://en.wikipedia.org/wiki/Brucellosis. Accessed on January 29, 2016
  23. Hunt A, Bothwell P. Histological findings in human brucellosis. J Clin Pathol. 1967; 20: 267-272