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Brucellosis
Definition
Brucellosis, previously known as Malta fever, Mediterranean fever, or undulant fever, is a zoonotic disease caused by bacteria of the genus Brucella . Human infection, which has protean manifestations, is acquired via direct contact, ingestion, or inhalation. Most disease is acquired by eating unpasteurized dairy products or undercooked meat. Occupational infection typically occurs by inhalation, inadvertent exposure to live attenuated vaccines, or through contamination of exposed wounds and mucous membranes. Human-to-human transmission occurs but is rare. Brucellosis remains a significant public health and economic burden in many countries despite advances in detection, treatment, and prevention. In regions where the disease is endemic, brucellosis has far-reaching deleterious effects on humans and animals alike.
The Pathogen
Brucella is a slow-growing, small, aerobic, nonmotile, non-encapsulated, non–spore-forming, gram-negative coccobacillus. Brucella abortus (from cattle, bison, elk), B. suis (from pigs and feral swine), B. melitensis (from sheep, goats, and camels), and B. canis (from dogs) are the species that most commonly infect humans. Genetic analysis shows a high degree of homology among different species despite disparate preferred hosts. Virulence factors can also vary between and within species. Whole-genome sequencing shows that Brucella is closely related to saprophytic soil-dwelling bacteria, and some species within Ochrobactrum are genetically very similar to Brucella .
Epidemiology
More than 500,000 cases of brucellosis are reported yearly to the World Health Organization (WHO) from 100 countries, but the true incidence is estimated to be 10 to 25 times higher. B. melitensis infection accounts for most diagnosed cases owing to difficulties in immunizing free-range sheep and goats, which harbor this species. Most cases occur in the Mediterranean region, Latin America, the Arabian Gulf, China, and the Indian subcontinent. B. abortus infection occurs worldwide and is responsible for most outbreaks in Mexico, China, Greece, and Brazil. B. suis is found in the United States, South America, and Southeast Asia. B. canis infection occurs in North America, South America, Japan, and Central Europe. In Africa, high rates of Brucella seropositivity have been reported in local wildlife and in communities that keep livestock and consume unpasteurized milk.
In animals, brucellosis is a chronic infection that can persist throughout life. Control programs in animals have decreased human brucellosis dramatically in the United States from more than 6000 cases in 1947 to about 80 to 120 cases annually, with most cases reported in Texas, California, Arizona, and Florida.
Brucella infection in the United States occurs mostly through direct contact with animals or animal secretions in high-risk groups, including slaughterhouse workers, farmers, dairy workers, and veterinarians. Laboratory workers handling infected animals or Brucella cultures are also at risk. More than one half of reported cases are associated with meat processing, particularly from “kill areas.” Many cases of B. abortus infection in veterinarians are from accidental exposure to live vaccines used to immunize livestock. Human infections in hunters of feral swine occur sporadically. Imported goat milk and cheese from Mexico (unpasteurized) is an important source of B. melitensis infection. Brucellosis contracted abroad may not become symptomatic until the traveler returns. Childhood brucellosis, which occurs mostly in school-aged children, accounts for 3 to 10% of all reported cases worldwide.
Human-to-human transmission is rare and has occurred through sexual transmission, breastfeeding, blood transfusion, bone marrow transplantation, nosocomial exposure, and perinatally. For example, a family cluster of brucellosis in China involved vertical transmission and sexual transmission following occupational exposure of the index case.
Pathobiology
Pathogenesis
Entry of Brucella organisms into humans is usually through the mucosal route, via ingestion or inhalation. The bacteria then translocate through the intestinal mucosa or the respiratory epithelium. Oral, conjunctival, and direct skin inoculation can also occur. Brucella in naïve individuals induces a delayed inflammatory response, with mostly macrophages and dendritic cells involved in the early response. Granulomas composed of lymphocytes, infected macrophages, and dendritic cells eventually form. Phagocytosed Brucella subsequently spread to regional lymph nodes. If host defenses within the lymph nodes are overwhelmed or the burden of infection is high, bacteremia follows. The usual incubation period from infection to bacteremia is 2 to 4 weeks. Bacteremia is accompanied by phagocytosis of free Brucella organisms by macrophages, primarily in the spleen, liver, and bone marrow, where small, noncaseating granulomas form and can serve as persistent sources of infection.
Brucella organisms avoid initial detection by the host through multiple mechanisms. Its cell wall lipopolysaccharide differs significantly from most other bacteria in two important ways: Brucella has very little effect on toll-like receptor type 4 (TLR4) activation, and it is resistant to complement activation. In addition, Brucella deploys a protein that interferes with TLR signaling. Upon successful entry into the host, about 10% of Brucella organisms in phagosomes are able to survive acidification and lysosome fusion to form an endosomal Brucella -containing vacuole, thereby maintaining a persistent presence. To replicate, Brucella organisms intercept traffic between the endoplasmic reticulum and the Golgi apparatus.
Apart from structurally helping to maintain cell envelope integrity, Brucella outer membrane proteins Omp25/Omp31 contribute to virulence by mediating direct interactions between the brucellae and mammalian cells. Other important virulence factors that enable pathogenic Brucella to survive the hostile intracellular niche include catalase, superoxide dismutase, alkyl hydroperoxide reductase, cytochrome oxidase, nitric oxide reductase, Brucella virulence factor A, and the Nramp1 gene.
Inflammation from the innate host immune response is likely the main driver of pathology because no secreted proteolytic enzymes or bacterial toxins have been found. Brucella induces the production of host proinflammatory cytokines and metalloproteinases, which cause tissue damage, particularly in osteoarticular areas of the body.
Immunity
Innate immunity to Brucella is mediated by activation of toll-like receptors, which produce inflammatory cytokines and recruit phagocytic cells, such as macrophages and dendritic cells, which attempt to control the initial infection and activate adaptive immunity. Platelets also release cytokines, which recruit more monocytes and macrophages in an attempt to clear infection.
Similar to other intracellular organisms, cell-mediated immunity is the predominant adaptive immunologic response to Brucella . Macrophages, activated with T helper 1 (T H 1)–type cytokines (most importantly interferon-γ, tumor necrosis factor-α, interleukin-1, and interleukin-12), kill Brucella . Antibody production seems to play a peripheral role in clearing infection and is not considered essential. Increasing evidence suggests that Brucella -infected neutrophils dampen adaptive immunity and may act as “Trojan horses” that aid dispersal of bacterial infection throughout the body.
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