Brucellosis pathophysiology

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:

Transmission

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

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.

• On entry into the body, Brucellae multiply in the neutrophilic granulocytes and monocytes, initially in lymph nodes, which is followed by systemic hematogenous spread resulting in multiple localizing infection

Immune response

Brucellosis elicits both humoral and cell-mediated immune responses:

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

• Tumor necrosis factor α (TNF-α) produce 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-gamma.
• Cytokines such as interleukin (IL) 12 promote production of Interferon γ (IFN-γ) responses. IFN-γ, which drives TH1-type responses and stimulates macrophage activation. Cytokines, which include , IL-6, IL-4and IL-10, down-regulate the protective response.

Pathogenesis

The pathogenesis of brucellosis is complex and not fully understood:

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 phagosome–lysosome 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.
• 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

• Brucella is not an opportunistic infection.
• Severity of infection in patients with HIV depends on number of CD4+T lymphocytes.

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”.
• Common findings on microscopic histopathological analysis of the liver include:
  • Granulomas with centrilobular necrosis or focal necrosis and parenchyma destruction.

• 

  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”.

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  Histopathology of guinea pig liver in experimental Brucella suis infection. Granuloma with necrosis.