Fusobacterium Infection And Immunity

Itzhak Brook, Department of Pediatrics, Georgetown University, Washington DC, USA

Fusobacterium spp. are gram-negative, nonsporulat-ing, nonmotile and, generally, moderately long filamentous organisms, sometimes slightly elongated spindle-shaped rods, that belong to the family Bac-teroidaceae. They are weak fermenters or unable to ferment sugar. The ability of Fusobacterium spp. to produce N-butyric acid without isobutyric or isovaleric acids differentiates them from the other Bacter-oidaceae. There are currently 12 known species of Fusobacterium. The species seen most often in clinical infections include F. nucleatum (currently divided into four subspecies), F. necropborum, F. gonidiafor-mans, F. naviforme, F. mortiferum, F. necrogenes, F. ulcerans, F. russii and F. varium. Of these, F. nucleatum is best able to produce the enzyme ^-lactamase.

Fusobacterium spp. are part of the normal oral, gastrointestinal and female genital tract flora; these sites, therefore, are the most common origin of infections that involve these organisms. The organisms are often recovered mixed with other anaerobes and aerobes in polymicrobial infections that are often synergistic.

Fusobacterium spp. produce lipopolysaccharide, endotoxin, neutrophil-cytotoxic substances and DNAase, which have all been associated with virulence. F. nucleatum can adhere to lymphocytes and facilitate their activity. The adherence is believed to be mediated by lecitin-like ligands. It can be inhibited by N-acetylgalactosamine, lactose and a- and (3-methylgalactoside. F. nucleatum also has an immunosuppressive effect on human peripheral blood lymphocytes. Such an effect may enhance the pathogenicity of the organisms as well as other copathogens.

As with other anaerobic bacteria, the ability of Fusobacterium spp. to induce subcutaneous abscesses correlates with the presence of a mucopolysaccharide layer in the cell wall. The ability to produce subcutaneous abscesses in experimental animals could, therefore, be an indication of the organism's virulence, as has been noticed with other anaerobic strains.

Factors associated with infections involving Fusobacterium spp. include break-up of the normal cutaneous and mucosal defenses, as may occur in Epstein-Barr virus pharyngitis, tissue injury caused by surgery or trauma, and impaired blood supply caused by microvascular disease. Moreover, the production of proteolytic enzymes by Fusobacterium spp. may allow early invasion of regional veins, even without tissue necrosis. Furthermore, the low oxidation-reduction potential and oxygen-free environment of devitalized tissue allows growth of these organisms.

Support for the pathogenic role of Fusobacterium spp. may be derived from in vivo studies that have demonstrated their synergistic potential with other anaerobic and aerobic bacteria. With few exceptions, the presence of Fusobacterium spp. enhanced the growth of other aerobic and anaerobic bacteria. Bacterial synergy was demonstrated between Fusobacterium spp. and anaerobic cocci. Staphylococcus aureus and Pseudomonas aeruginosa by means of a subcutaneous abscess model in mice. In this model, Fusobacterium spp. enhanced the formation of abscesses and mortality when inoculated with the other organisms.

The spectrum of infections in which Fusobacterium spp. play a pathogenic role include bacteremia, head and neck infections (such as chronic otitis media, sinusitis and mastoiditis, peritonsillar and retropharyngeal abscesses, Vincent's angina, gingival and dental infections), pulmonary infections (aspiration pneumonia, lung abscesses and empy ema), intracranial infections (meningitis and intracranial abscesses), gastrointestinal infections (peritonitis, hepatic and abdominal abscesses), osteomyelitis, urogenital (prostatic and female genital abscesses, amnionitis) as well as skin and soft tissue infections, especially around the oropharyngeal area.

Fusobacterium spp. have been associated with single or polymicrobial bacteremia, of primarily oropharyngeal origin, that may accompany cervical septic thrombophlebitis, necrotizing pneumonia or metastatic infection, known as Lemierre's disease.

F. nucleatum (currently divided into four subspecies) is the predominant fusobacterium found in the oral flora and in human infections. It has been associated with dental plaques, necrotizing gingivitis, acute ulcerative gingivitis (Vincent's angina) and periodontitis. It is also the major fusobacterium recovered from all head and neck infections and their sequelae.

F. nucleatum and related species can be recovered in a variety of mixed infection in animals, including bovine pyometra, necrobacillosis of the jaw in macropods and feline abscesses following cat bites.

Elevated antibodies to protein antigens of F. nucleatum were found in patients with periodontal disease, peritonsillar cellulitis and abscesses, infectious mononucleosis and acute streptococcal, nonstrepto-coccal and recurrent tonsillitis. It is possible that the increase in antibodies to these outer membrane proteins - which may contribute to bacterial attachment - may signify a potential direct or indirect pathogenic role for this organism in these infections.

F. necrophorum (currently divided into two subspecies) is the second most common pathogen in humans. It is found in pharyngeal and tonsillar infection associated with bacteremia, otitis, pneumonia, liver and colonic infections. It has a variety of virulence factors that makes it a potentially greater pathogen than other fusobacteria. These include a leucociclin, hemolysin, a hemagglutinin, a lipase, a DNAase, a proteinase and a lipopolysaccharide endotoxin.

F. necrophorum (divided into two biovars, A and B) is part of the normal gastrointestinal flora of herbivores and other species, and can cause endogenous infection in these hosts as well as in humans. Necrobiosis in humans (generally due to biovar B) is a throat infection followed by systemic spread and metastatic abscesses. Necrobacillosis infections in animals (generally due to biovar A) are usually polymicrobial and include coagulative necrosis and abscesses and can cause mortality. Necrobacillosis generally occurs in the oral cavity, liver and foot. Bovine hepatic necrosis is hematogenous, originating from minimal lesions and foot rot. Necrobacillosis can affect wild and domestic animals.

Necrobacillosis is often a synergistic infection. In vivo synergy between F. necrophorum and Actinomyces pyogenes, Escherichia coli and Staph, aureus was demonstrated in mice, and growth stimulation between F. necrophorum and A. pyogenes was found in vitro.

Delayed-type hypersensitivity to F. necrophorum could be induced in mice, and leukotoxin-specific antibodies can be detected in cattle with induced or naturally-acquired hepatic abscess due to this organism. Antibodies to F. necrophorum can be detected after infection using passive hemagglutination and enzyme-linked immunosorbent assays. However, protection against reinfection is not always achieved after natural infection or vaccination with a toxoid prepared from the cytoplastic fraction of F. necrophorum. Even utilization of an extreme method of immunization, by producing a severe subcutaneous F. necrophorum infection followed by curative therapy with metronidazole, produced only slight protection. That F. necrophorum is naturally a weak immunogenic pathogen is therefore plausible.

See also: Bacteria, immunity to; Bacterial cell walls; Bacteroides, infection and immunity.

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