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Pathogenesis

Natural infection is by inhalation and results in bronchiolitis and pneumonia. Some experimental studies have shown that infection of cattle by endotracheal intubation resulted in chronic disease, while natural infection by close contact with infected animals induced severe infection that was more likely to result in mortality, although other studies indicated that the only difference observed was in the incubation period, which was more variable in naturally infected cattle. It appears that the route of infection determines the outcome. While the typical respiratory lesions result from infection via the respiratory route, subcutaneous inoculation results in the development of an invasive local oedema known as the ‘Willems reaction’ after the person who performed the first inoculation trials in 1852. Intraperitoneal inoculation results in peritonitis. In natural infection the lesions are confined to the lungs in both the acute and chronic forms of the disease, apart from the arthritis that has been described in calves.

The result of the multiplication of MmmSC in the lung is severe inflammation that causes respiratory distress and can result in the death of 30 per cent or more of the affected cattle. The pathogenesis of CBPP has not been fully elucidated because of the high cost of experimental work in cattle and the lack of a laboratory animal model. Given the severity of the disease, there are also ethical considerations. However, individual molecular mechanisms that contribute to virulence can be studied using a variety of techniques such as in vitro immunoassays, cellular studies and mouse infection bioassays.

Actions involved in virulence include evasion of the host’s immune system, tight adhesion to the surface of the host’s cells, dissemination and persistence in the host, efficient importation of required nutrients and induction of cytotoxicity in the host. Mycoplasmas have the smallest genomes of all self-replicating organisms. Complete sequencing of the genome of MmmSC in 2004 has revealed a lack of genes encoding primary virulence factors like toxins, cytolysins and invasins that are generally found in other bacteria, so that virulence depends on intrinsic metabolic and catabolic functions as well as surface proteins and their regulation. For example, recent studies have confirmed that the production of large amounts of hydrogen peroxide (H2O2) due to a gene that facilitates active uptake of glycerol, which is phosphorylated and then metabolised further to release H2O2, which is then transported into the host cell, is important for virulence. The MmmSC strain that caused the outbreaks of CBPP in Europe in the last decades of the 20th century lacked the genes necessary for this process and caused mild disease. Tight adhesion of the pathogen to the host cell is required for the H2O2 to be released into the host cell and produce a cytotoxic effect, since a strain that produced large amounts of H2O2 but did not adhere well to the surface was unable to cause cytotoxicity.

Evasion of the host immune system and the ability to disseminate and persist in the host appear to be related to effects of the pathogen on cells responsible for the immune response. In vitro experiments indicated that MmmSC is capable of inducing apoptosis in all types of blood leucocytes (all lymphocyte and monocyte/granulocyte subsets), although no genetic basis for this was found; production of TN-alpha by MmmSC may be involved, as in association with NF-kappa-B it is associated with induction of apoptosis Furthermore, the progression of clinical signs in acute disease was associated with decreased interferon production by peripheral blood mononuclear cells.  

Virulence appears to depend strongly on surface antigens that protect the organism and cause various reactions in the host. The capsular polysaccharide galactan has cytopathic and vaso-active effects and contributes to the ability of the organism to spread and persist in the host, probably owing to its ability to protect the organism. Surface lipoproteins have been identified that are strongly antigenic and are believed to have important roles in virulence. Several have been identified as promising candidates for mediation of adhesion, including a variable surface lipoprotein that appears to be specific to MmmSC. Although adhesins have been found in other mycoplasmas and are considered to be central to their pathogenicity, enabling transport into the host cell of substances that induce the inflammatory reaction as well as being responsible for species specificity and tissue tropism, none have to date been found in MmmSC. Lipoproteins are also considered to play an important role in immunopathogenicity. The membrane protein L-alpha-glycerophosphate oxidase (GlpO) has been identified as playing a central role in cytotoxicity by catalysing the oxidation of glycerol-3-phosphate, which results in the release of H2O2. The presence of H2O2 and/or reactive oxygen species in the host cell may cause direct damage as well as triggering an inflammatory reaction. Some of the differences in virulence between strains including vaccine and field strains may be explained by a single nucleotide polymorphism in the gene encoding 6-phospho-beta-glucosidase (Bgl) that determines the isoform in which Bgl occurs.