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{{Brucellosis}}
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== Overview ==
 
''[[Brucella|Brucellosis]]'' is a [[zoonotic]] disease, [[humans]] could be infected by eating undercook meat or raw [[Dairy product|dairy]] products, inhalation of the [[bacteria]] and direct contact of bacteria with [[skin]] [[wounds]] or [[Mucous membranes|mucous membranes.]] Following transmission, [[white blood cells]] phagocyte the pathogen and transports it via hematologic or [[Lymphatic system|lymphatic route]] to different organs, specially to those of the [[reticuloendothelial system]].
==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]].<ref name="pmid9204307">{{cite journal| author=Corbel MJ| title=Brucellosis: an overview. | journal=Emerg Infect Dis | year= 1997 | volume= 3 | issue= 2 | pages= 213-21 | pmid=9204307 | doi=10.3201/eid0302.970219 | pmc=PMC2627605 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9204307  }} </ref><ref name="aa">Brucelosis. Wikipedia. https://es.wikipedia.org/wiki/Brucelosis. Accessed on February 2, 2016</ref>
 
== Pathophysiology==


The pathophysiology of brucellosis  may be described in the following steps:
== Pathophysiology ==
''[[Brucella|Brucellosis]]'' is a [[zoonotic]] disease, [[humans]] could be infected by eating undercook meat or raw [[Dairy product|dairy]] products, inhalation of the [[bacteria]] and direct contact of bacteria with [[skin]] [[wounds]] or [[Mucous membranes|mucous membranes.]] Following transmission, [[white blood cells]] phagocyte the pathogen and transports it via hematologic or [[Lymphatic system|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|monocytic cel]]<nowiki/>l, supressing [[Lysosome|phagosome-lysosome fusion]] and internalizing bacteria into [[endoplasmic reticulum]]. The pathophysiology of Brucellosis can be described in the following steps:<ref name="pmid15930423">{{cite journal| author=Pappas G, Akritidis N, Bosilkovski M, Tsianos E| title=Brucellosis. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 22 | pages= 2325-36 | pmid=15930423 | doi=10.1056/NEJMra050570 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15930423  }}</ref><ref name=":0">{{Cite web|url=https://www.cdc.gov/brucellosis/transmission/index.html|title=CDC|date=|access-date=|website=|publisher=|last=|first=}}</ref><ref name="pmid8698508">{{cite journal| author=Zhan Y, Liu Z, Cheers C| title=Tumor necrosis factor alpha and interleukin-12 contribute to resistance to the intracellular bacterium Brucella abortus by different mechanisms. | journal=Infect Immun | year= 1996 | volume= 64 | issue= 7 | pages= 2782-6 | pmid=8698508 | doi= | pmc=174139 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8698508  }} </ref><ref name="pmid1574477">{{cite journal| author=Larralde de Luna M, Raspa ML, Ibargoyen J| title=Oral-facial-digital type 1 syndrome of Papillon-Léage and Psaume. | journal=Pediatr Dermatol | year= 1992 | volume= 9 | issue= 1 | pages= 52-6 | pmid=1574477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1574477  }} </ref><ref name="pmid2915152">{{cite journal| author=Gazapo E, Gonzalez Lahoz J, Subiza JL, Baquero M, Gil J, de la Concha EG| title=Changes in IgM and IgG antibody concentrations in brucellosis over time: importance for diagnosis and follow-up. | journal=J Infect Dis | year= 1989 | volume= 159 | issue= 2 | pages= 219-25 | pmid=2915152 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2915152  }} </ref><ref name="pmid10858243">{{cite journal| author=Arenas GN, Staskevich AS, Aballay A, Mayorga LS| title=Intracellular trafficking of Brucella abortus in J774 macrophages. | journal=Infect Immun | year= 2000 | volume= 68 | issue= 7 | pages= 4255-63 | pmid=10858243 | doi= | pmc=101738 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10858243  }} </ref><ref name="pmid12414154">{{cite journal| author=Boschiroli ML, Ouahrani-Bettache S, Foulongne V, Michaux-Charachon S, Bourg G, Allardet-Servent A et al.| title=Type IV secretion and Brucella virulence. | journal=Vet Microbiol | year= 2002 | volume= 90 | issue= 1-4 | pages= 341-8 | pmid=12414154 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12414154  }} </ref><ref name="pmid15694858">{{cite journal| author=Lapaque N, Moriyon I, Moreno E, Gorvel JP| title=Brucella lipopolysaccharide acts as a virulence factor. | journal=Curr Opin Microbiol | year= 2005 | volume= 8 | issue= 1 | pages= 60-6 | pmid=15694858 | doi=10.1016/j.mib.2004.12.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15694858  }} </ref><ref name="pmid12414174">{{cite journal| author=DelVecchio VG, Kapatral V, Elzer P, Patra G, Mujer CV| title=The genome of Brucella melitensis. | journal=Vet Microbiol | year= 2002 | volume= 90 | issue= 1-4 | pages= 587-92 | pmid=12414174 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12414174  }} </ref><ref name="pmid11782541">{{cite journal| author=Moreno E, Moriyon I| title=Brucella melitensis: a nasty bug with hidden credentials for virulence. | journal=Proc Natl Acad Sci U S A | year= 2002 | volume= 99 | issue= 1 | pages= 1-3 | pmid=11782541 | doi=10.1073/pnas.022622699 | pmc=117501 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11782541  }} </ref><ref name="pmid12414149">{{cite journal| author=Gorvel JP, Moreno E| title=Brucella intracellular life: from invasion to intracellular replication. | journal=Vet Microbiol | year= 2002 | volume= 90 | issue= 1-4 | pages= 281-97 | pmid=12414149 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12414149  }} </ref><ref name="pmid12525425">{{cite journal| author=Ko J, Splitter GA| title=Molecular host-pathogen interaction in brucellosis: current understanding and future approaches to vaccine development for mice and humans. | journal=Clin Microbiol Rev | year= 2003 | volume= 16 | issue= 1 | pages= 65-78 | pmid=12525425 | doi= | pmc=145300 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12525425  }} </ref><ref name="pmid12414158">{{cite journal| author=Dornand J, Gross A, Lafont V, Liautard J, Oliaro J, Liautard JP| title=The innate immune response against Brucella in humans. | journal=Vet Microbiol | year= 2002 | volume= 90 | issue= 1-4 | pages= 383-94 | pmid=12414158 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12414158  }} </ref>


'''Transmission:'''
=== Transmission===
According to CDC, humans are generally infected with Brucellosis in one of the following three ways:<ref name="pmid15930423" /><ref>{{Cite web|url=CDC|title=https://www.cdc.gov/brucellosis/transmission/index.html|last=|first=|date=|website=|publisher=|access-date=}}</ref>
{| class="wikitable"
{| class="wikitable"
! colspan="2" |Humans are generally infected with brucellosis in one of three ways
! colspan="2" |ROUTE OF TRANSMISSION
|-
|-
|[[Gastrointestinal]]
|
|
=== Eating undercooked meat or consuming unpasteurized/raw dairy products ===
Eating undercooked meat or consuming [[Unpasteurized milk|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.
|-
|-
|[[Inhalation]]
|
|
=== Breathing in the bacteria that cause brucellosis (inhalation) ===
[[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.
|-
|-
|[[Cutaneous]]
|
|
=== Bacteria entering the body through skin wounds or mucous membranes ===
[[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
|-
|-
| colspan="2" |
|Other modes of transmission
* Person-to-person spread of brucellosis is extremely rare.
|
* Infected mothers who are breast-feeding may transmit the infection to their infants.
*Person-to-person spread of [[brucellosis]] is extremely rare.
* Sexual transmission has been rarely reported.
*Infected mothers who are breast-feeding may transmit the infection to their infants.
* While uncommon, transmission may also occur via tissue transplantation or blood transfusions.
*Sexual transmission has been rarely reported.
*While uncommon, [[transmission]] may also occur via [[Transplantation|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. <ref>Mantur BG, Amarnath SK, Shinde RS. Review of clinical and laboratory features of human brucellosis. Indian J Med Microbiol 2007; 25:188.</ref><ref>Fiori PL, Mastrandrea S, Rappelli P, Cappuccinelli P. Brucella abortus infection acquired in microbiology laboratories. J Clin Microbiol 2000; 38:2005.</ref>
=== '''Incubation''' ===
[[Incubation period]] of brucellosis varies from one to four weeks. But occasionally, it may be as long as several months. 


'''Dissemination'''
=== '''Dissemination''' ===
Following transmission, brucellae is ingested by [[macrophages]] and [[Polymorphonuclear cells|polymorphonuclea]]<nowiki/>r cells. On ingestion, they replicate [[Intracellular|intracellularly]] inside the lysed cells and disseminate systemically. 


Following transmission, brucellae is ingested by macrophages and polymorphonuclear cells. On ingestion, they replicate intracellularly inside the lysed cells, infecting the other cells or disseminating  systemically. <ref>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.</ref>
===Seeding===
* On [[transmission]], [[bacteria]] is actively [[phagocytosed]]  by neurophilic [[granulocytes]] and [[monocytes]].


=== Seeding ===
*On entry into the body, [[Brucella|brucellae]] multiply in the [[Neutrophil|neutrophilic]] [[granulocytes]] and [[monocytes]], initially in [[lymph nodes]], which is followed by systemic hematogenous spread resulting in multiple localizing [[infection]]
* On transmission, Neutrophilic granulocytes and monocytes actively phagocytosed the bacteria, Initial attachment takes place via specific receptors, including Fc, C3, fibronectin, and mannose-binding proteins.
* Opsonized bacteria trigger an oxidative burst inside phagocytes. Unopsonized bacteria are internalized via similar receptors but at much lower efficiency. Smooth lipopolysaccharide (LPS), β-cyclic glucan, and possibly an invasion-attachment protein (IalB) are involved in this process.
* Initial intracellular replication of brucellae takes place within cells of the lymph nodes draining the point of entry. Followed by systemic hematogenous spread, resulting in chronic localizing infection at almost any site, although the reticuloendothelial system, musculoskeletal tissues, and genitourinary system are most frequently targeted.


=== Immune response ===
===Immune response===
Brucellosis elicits both humoral and cell-mediated immune responses:<ref name="pmid27672085">{{cite journal| author=Khan M, Harms JS, Marim FM, Armon L, Hall CL, Liu YP et al.| title=The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response. | journal=Infect Immun | year= 2016 | volume= 84 | issue= 12 | pages= 3458-3470 | pmid=27672085 | doi=10.1128/IAI.00531-16 | pmc=5116723 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27672085  }}</ref>
Brucellosis elicits both [[Humoral immunity|humoral]] and [[Cell-mediated immunity|cell-mediated]] [[immune]] responses:<ref name="pmid15930423" /><ref name=":0" /><ref name="pmid8698508" /><ref name="pmid1574477" /><ref name="pmid2915152" /><ref name="pmid10858243" /><ref name="pmid12414154" /><ref name="pmid15694858" /><ref name="pmid12414174" /><ref name="pmid27672085">{{cite journal| author=Khan M, Harms JS, Marim FM, Armon L, Hall CL, Liu YP et al.| title=The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response. | journal=Infect Immun | year= 2016 | volume= 84 | issue= 12 | pages= 3458-3470 | pmid=27672085 | doi=10.1128/IAI.00531-16 | pmc=5116723 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27672085  }}</ref><ref name="pmid159304233">{{cite journal| author=Pappas G, Akritidis N, Bosilkovski M, Tsianos E| title=Brucellosis. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 22 | pages= 2325-36 | pmid=15930423 | doi=10.1056/NEJMra050570 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15930423 }}</ref>
====Humoral immune response====
* [[Humoral immune system|Humoral]] response has a limited role in protecting host from [[Brucellosis|Brucellae]].
* On activation, [[Chronic lymphocytic leukemia|B-cell]] produce [[IgM]] class [[antibody]], which is followed by [[IgG]] antibodies .
* [[Antibodies]] promote clearance of extracellular [[bacteria]] and facilitate [[phagocytosis]] of the Brucellae.


==== Humoral immune response ====
====Cell mediates immune response====
Antibodies promote clearance of extracellular brucellae by bactericidal action and by facilitation of phagocytosis by polymorphonuclear and mononuclear phagocytes; however, antibodies alone cannot eradicate infection.
*Tumor necrosis factor α ([[TNF-α]]) produces on activation of [[cell mediated immunity]], stimulates [[T lymphocytes]] and [[macrophages]], which help in eliminating intracellular [[brucellae]]. Virulent brucellae tend to suppress the activity of tumor necrosis factor α (TNF-α) and [[IFN|IFN-gamma]].
*[[Cytokines]] such as [[Interleukin 12|interleukin (IL) 12]] promote production of Interferon γ ([[Interferon|IFN-γ]]) responses. IFN-γ, which drives [[TH1]]-type responses and stimulates [[macrophage]] activation. [[Cytokines]], which include , [[IL-6]], [[IL-4]]<nowiki/>and [[IL-10]], down-regulate the protective response.


==== Cell-mediated immune response ====
==Pathogenesis==
* Tumor necrosis factor α (TNF-α) produced early in the course of infection stimulates T-cytotoxic lymphocytes and activates macrophages, which can kill intracellular brucellae
The pathogenesis of brucellosis is complex and not fully understood:<ref name="pmid15930423" /><ref name=":0" /><ref name="pmid8698508" /><ref name="pmid1574477" /><ref name="pmid2915152" /><ref name="pmid10858243" /><ref name="pmid12414154" /><ref name="pmid15694858" /><ref name="pmid12414174" /><ref>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.</ref><ref>Gorvel JP, Moreno E. Brucella intracellular life: from invasion to intracellular replication. Vet Microbiol 2002; 90:281.</ref><ref name="pmid159304234">{{cite journal| author=Pappas G, Akritidis N, Bosilkovski M, Tsianos E| title=Brucellosis. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 22 | pages= 2325-36 | pmid=15930423 | doi=10.1056/NEJMra050570 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15930423  }}</ref>
* Virulent brucella cells can suppress the TNF-α response, and control of infection in this situation depends on macrophage activation and interferon γ (IFN-γ) responses. Cytokines such as interleukin (IL) 12 promote production of IFN-γ, which drives TH1-type responses and stimulates macrophage activation. Inflammatory cytokines, including IL-4, IL-6, and IL-10, downregulate the protective response.


=== Pathogenesis ===
By avoiding [[innate immunity]], [[Brucella infection|brucella]] survive with in [[Monocytic|monocytic cells]].
The pathogenesis of brucellosis involve the following:<ref>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.</ref><ref>Gorvel JP, Moreno E. Brucella intracellular life: from invasion to intracellular replication. Vet Microbiol 2002; 90:281.</ref>
*Endotoxic [[lipopolysaccharide]] (LPS), plays a key role in survival of bacteria inside [[monocytic]] cell.
* Brucella, avoid triggering of innate immunity, permitting survival within monocytic cells.
*[[LPS]] helps in survival of the [[bacteria]] inside the [[monocytic]] cell, by suppressing [[phagosome]]–[[lysosome]] fusion, internalizing bacteria into [[endoplasmic reticulum]] and inhibiting [[apoptosis]] of [[infected]] cell.
* Endotoxic lipopolysaccharide LPS, plays a key role in pyrogenicity and in resistance to phagocytosis and serum killing in the nonimmune host.
*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]]
* LPS plays a  key role in suppressing phagosome–lysosome fusion and diverting the internalized bacteria into vacuoles located in endoplasmic reticulum, where intracellular replication takes place.
*Cu-Zn [[superoxide dismutase]], produced by brucellae, gives them resistance from [[reactive oxygen]] intermediates.
* Type IV secretion system (VirB) that regulates intracellular survival and trafficking has been identified.
*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.<ref name="pmid159304232">{{cite journal| author=Pappas G, Akritidis N, Bosilkovski M, Tsianos E| title=Brucellosis. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 22 | pages= 2325-36 | pmid=15930423 | doi=10.1056/NEJMra050570 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15930423  }}</ref>
* Brucellae, produce acid-stable proteins that facilitate the organisms’ survival in phagosomes and may enhance their resistance to reactive oxygen intermediates.
*[[Hemolysin|Hemolysins]] help the [[bacteria]] to be realeased from a [[cell]] and induce cell [[necrosis]].
* A type III secretion system based on modified flagellar structures also has been inferred, although not yet confirmed.
==Genetics==
* Virulent brucellae are resistant to defensins and produce a Cu-Zn superoxide dismutase that increases their resistance to reactive oxygen intermediates.
There is no known genetic association to Brucellosis.
* A hemolysin-like protein may trigger the release of brucellae from infected cells.


=== Genetics ===
== Microscopic Pathology ==
There is no known genetic association to brucellosis.
[[File:Brucellosis histopathology.png|center|thumb|673x673px|Brucella spp. are poorly staining, small gram-negative coccobacilli (0.5-0.7 x 0.6-1.5 µm), and are seen mostly as single cells and appearing like “fine sand”.- By Photo Credit:Content Providers(s): CDC/Courtesy of Larry Stauffer, Oregon State Public Health Laboratory - This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #1901.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, https://commons.wikimedia.org/w/index.php?curid=723156]]
[[File:Brucella granuloma with necrosis.png|center|thumb|705x705px|Histopathology of guinea pig liver in experimental Brucella suis infection. Granuloma with necrosis. - Public Domain, https://commons.wikimedia.org/w/index.php?curid=2255655]]


=== Associated conditions ===
=== Gross pathology ===
=== Microscopic Pathology ===
*[[Brucella|''Brucella spp''.]] are poorly staining, small gram-negative coccobacilli (0.5-0.7 x 0.6-1.5 µm).
*[[Brucella|''Brucella spp.'']] are seen mostly as single cells and appearing like “fine sand”.<ref name="a2">Brucellosis. Wikipedia. https://en.wikipedia.org/wiki/Brucellosis. Accessed on January 29, 2016</ref>
*On microscopic histopathological analysis of the liver, common findings are:
**[[Granulomas]] with centrilobular necrosis or focal necrosis and parenchyma destruction.<ref>Hunt A, Bothwell P. Histological findings in human brucellosis. ''J Clin Pathol''. 1967; 20: 267-272</ref>
**
<gallery>
Image:Brucella-histo.jpg|thumb|200px|Brucella spp. are poorly staining, small gram-negative coccobacilli (0.5-0.7 x 0.6-1.5 µm), and are seen mostly as single cells and appearing like “fine sand”.
Image:Bruce-granulomanecrosis.jpg|thumb|200px|Histopathology of guinea pig liver in experimental Brucella suis infection. Granuloma with necrosis.
</gallery>
==Reference==
==Reference==
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Latest revision as of 20:45, 29 July 2020


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

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Overview

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.

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]

ROUTE OF TRANSMISSION
Gastrointestinal

Eating undercooked meat or consuming unpasteurized/raw dairy products

Inhalation

Breathing in the bacteria that cause brucellosis (inhalation)

Cutaneous

Bacteria entering the body through skin wounds or mucous membranes

Other modes of transmission

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

Immune response

Brucellosis elicits both humoral and cell-mediated immune responses:[1][2][3][4][5][6][7][8][9][15][16]

Humoral immune response

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.

Genetics

There is no known genetic association to Brucellosis.

Microscopic Pathology

+/−, Public Domain, https://commons.wikimedia.org/w/index.php?curid=723156
Histopathology of guinea pig liver in experimental Brucella suis infection. Granuloma with necrosis. - Public Domain, https://commons.wikimedia.org/w/index.php?curid=2255655

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.
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