23 Mauricio Navarro and Francisco A. Uzal Infectious necrotic hepatitis (INH), also known as black disease, is an acute and highly lethal disease of sheep caused by Clostridium novyi type B. It may also affect cattle, and rarely horses and dogs. The disease is clinically and pathologically similar to bacillary hemoglobinuria (BH) and therefore only those aspects that are specific to INH will be emphasized here. Readers should refer to Chapter 22 for common features of these two diseases. C. novyi is an anaerobic, Gram-positive, spore-forming rod, which is classified into four types (A, B, C, and D) based on the production of toxins, which are fully described in Chapter 4. Briefly, C. novyi type A produces alpha toxin (TcnA), which is thought to be the main virulence factor of this microorganism, and gamma toxin, a non-lethal phospholipase. C. novyi type A is responsible for gas gangrene of man and animals, acting alone or in combination with other clostridia. C. novyi type B produces mainly TcnA and beta toxin, which are thought to be the main virulence factors of the microorganism. However, the molecular Koch postulates have not been fulfilled and the definitive role of these toxins in the virulence of C. novyi type B remains, therefore, unconfirmed. The beta toxin of C. novyi type B is serologically indistinguishable from the beta toxin produced by C. haemolyticum (also known as C. novyi type D). TcnA is edema-inducing and lethal, while beta toxin is necrotizing and hemolytic, but is not usually produced in lethal amounts. The spores of C. novyi type B are very resistant to environmental factors and, as with C. haemolyticum, they can presumably remain latent in phagocytic cells of ruminants and possibly other species, mainly in the liver, but also in the spleen and bone marrow; the microorganism can also be found in soil and as part of the intestinal microbiota. Finally, C. novyi type C is nontoxigenic and nonpathogenic. The pathogenesis of INH is similar to that of BH (Chapter 22). Both diseases are associated with initiating hepatic damage, usually induced by the migration of the immature forms of Fasciola hepatica and other liver flukes such as Dicrocoelium dendriticum and Fascioloides magna, which creates the anaerobic conditions for the germination of the spores and the proliferation of C. novyi type B, with the consequent production of toxins. In INH, the released TcnA acts on the actin cytoskeleton and the vimentin and tubulin systems of cells, inducing irreversible changes in cell morphology; additionally, the glycosyltransferase activity of TcnA has a role in modifying several small GTP-binding proteins (Chapter 4). Capillary endothelium is particularly affected by these mechanisms, which result in cell instability followed by an extensive infiltration of fluid into the connective tissue. Although the high resemblance between beta toxin in C. novyi type B and C. haemolyticum suggests a similar mechanism of virulence for these two microorganisms, the beta toxin gene is far less expressed in C. novyi type B than in C. haemolyticum.
Infectious Necrotic Hepatitis
Introduction
Etiology
Pathogenesis
Epidemiology
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