Brucellosis pathophysiology

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.^[1][2]

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 bacteria with skin wounds or mucous membranes. 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. Endotoxic lipopolysaccharide LPS, plays an important role in survival of bacteria inside monocytic cell, suprresing-lysosome fusion, and Internalizing bacteria into endoplasmic reticulum. The pathophysiology of brucellosis may be described in the following steps:

Transmissio

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
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. ^[3][4]

Dissemination

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. ^[5]

Seeding

• On transmission, Neutrophilic granulocytes and monocytes actively phagocytosed the bacteria
• On entry into the body, brucellae multiply in the neutrophilic granulocytes ad 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:^[6]

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 and facitlitate 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 brucellar tend to supress 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-4, IL-6, and IL-10, downregulate the protective response.

Pathogenesis

The pathogenesis of brucellosis involve the following:^[7][8]

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.
• Acid-stable proteins produced by brucella, facilitates the survival in phogosomes
• Cu-Zn superoxide dismutase, produced by brucellae, gives them resistance from reactive oxygen intermediates.

Genetics

There is no known genetic association to brucellosis.

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”.^[9]
• On microscopic histopathological analysis of the liver, common findings are:
  • Granulomas with centrilobular necrosis or focal necrosis and parenchyma destruction.^[10]
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  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.