Virulence Factors and Pathogenomics

Cell‐wall lipids of C. pseudotuberculosis were the first factors recognized to have properties that could contribute to pathogenesis. Extracted surface lipids had a lethal effect on mouse macrophages (Hard 1975) and it has recently been shown that the corynomycolic acids of the cell wall activate macrophages following sensing by the C‐type lectin receptor Mincle and the Toll‐like receptor 2 (Schick et al. 2017).

A PLD exotoxin is recognized as the principal virulence factor of C. pseudotuberculosis. PLD is essential for virulence; targeted PLD deletion mutant strains of C. pseudotuberculosis are completely avirulent (Hodgson et al. 1992). The PLD can hydrolyze sphingomyelin, weakening cell membranes and increasing vascular permeability, thereby favoring the systemic spread and establishment of infection (Pépin et al. 1989). The membrane damage caused by PLD has also been shown to inhibit the entry of calcium ions into T lymphocytes by inhibiting the Orai channel, thereby inhibiting the lymphocyte activation process (Combs and Lu 2015). PLD expression is regulated by environmental factors and has been shown to be highly expressed in cultured macrophages (McKean et al. 2007a, 2007b). Other C. pseudotuberculosis genes, such as a non‐ribosomal peptide synthetase and a propionyl CoA carboxylase, have been identified as upregulated in macrophages, indicating that they may have a role in maintenance of infections within macrophages (McKean et al. 2005).

A 40 kDa protein, CP40, originally identified as a serine protease but more recently shown to be an endo‐β‐N‐acetylglucosaminidase, may be a virulence factor involved in immune evasion (Wilson et al. 1995; Shadnezhad et al. 2016). Analysis of the genome of C. pseudotuberculosis strain FCR41 identified genes encoding putative virulence factors such as the SpaC protein characterized as a pilus protein capable of facilitating the host–pathogen interaction and delivery of virulence factors, serine proteases, neuraminidase H, nitric oxide reductase, and proteins involved in mycolic acid biosynthesis (Trost et al. 2010). As with many bacteria, iron acquisition is vital for C. pseudotuberculosis infection and spread. Mutation of an iron uptake system encoded by the fagBCD operon decreased the pathogenicity of the mutant strain in goats (Billington et al. 2002).

Whole‐genome analysis of C. pseudotuberculosis biovar ovis isolates has identified encoded proteins likely to be involved in adherence and iron uptake as potential virulence factors and has also characterized a series of pathogenic islands within the genomes (Blanco et al. 2020). Comparative genome analysis has not identified any differences in the carriage of virulence genes that could explain the differences between the different types of infection that C. pseudotuberculosis biovar equi can produce (Baraúna et al. 2017).

Pathogenesis

Infection by C. pseudotuberculosis commonly occurs through superficial wounds where the bacteria enter the host and then spreads via the lymphatic system to the lymph nodes and other organs. The invading bacteria are phagocytosed by neutrophils and macrophages, the bacteria multiply intracellularly, and then the host cells degenerate and die (Dorella et al. 2006). The uncontrolled growth of the bacteria inside the macrophages leads to a host response based on an attempt to restrict the infection through the formation of granulomas, characterized by the encapsulation of the infected cells (Batey 1986). Intracellular invasion by C. pseudotuberculosis does not induce the production of nitric oxide (Bogdan et al. 1997), and therefore the potentiation of phagocytosis by the adaptive immune response appears to be an important mechanism to eliminate the bacterium or at least contain C. pseudotuberculosis spread (Lan et al. 1998).

C. pseudotuberculosis classical and putative virulence factors that may be involved in pathogenesis are summarized in Figure 32.2. Considerable further work is needed to understand details of intracellular survival and other aspects of the pathogenesis of this infection.

Immunity

Protective immune responses against C. pseudotuberculosis are mainly based on cytokine activation of macrophages, interferon‐γ (IFN‐γ) stimulus derived from lymphocytes, leading to the death of phagocytosed microorganisms and lysis of infected cells, carried out by CD8+ cytotoxic T cells (Alves et al. 2007). The fundamental role of IFN‐γ was observed in rats, in which an increase in bacterial growth was detected after administration of anti‐IFN‐γ monoclonal antibodies (Lan et al. 1998). Gene expression analysis of leukocyte subpopulations present in granulomas has shown that several cytokines are expressed during infection, including interleukin 2 and interleukin 4 in draining lymph nodes, and tumor necrosis factor (TNF) and IFN‐γ at the inoculation site (Pépin et al. 1997). There is evidence that the production of IFN‐γ and TNF, stimulated by C. pseudotuberculosis, occurs through the mitogen‐activated protein kinase p38 and ERK 1/2 signaling pathways (de Souza et al. 2014).

Vaccines based on toxoids have been available for decades. Attenuated live strains of C. pseudotuberculosis, in which the PLD gene has been deleted or mutated to an inactive form, have also been shown to be effective (Hodgson et al. 1992, 1999). Commercially available vaccines are based mainly on toxoids, as seen in formulations of Glanvac^® (Zoetis), Websters^® cheesy gland vaccines (Virbac) and Biodectin^® (Fort Dodge Animal Health). Live attenuated vaccines are available in Brazil Vacina 1002^® (Labovet Produtos Veterinários) and Linfovac^® (Laboratórios Vencofarma do Brasil Ltda). Even though commercial vaccines are available, they only deliver partial protection against CLA, and there are differences in protection between sheep and goats (de Pinho et al. 2021).

Control

Bacterial isolation from animal lesions is the standard diagnostic approach for CLA. This approach is most easily applied to animals with superficial lesions, however animals often have internal forms of the disease and lesions cannot be easily accessed (Ribeiro et al. 2013). Immunological methods have therefore been developed to aid in the diagnosis of CLA. Throughout the years, a variety of immunological tests such as serum agglutination, complement fixation, hemolysis inhibition, and enzyme‐linked immunosorbent assay (ELISA), have been developed using different antigens. The currently used tests are based on the ELISA method, using antigen preparations such as secreted proteins (Seyffert et al. 2010; Rebouças et al. 2013), native exotoxin (Baird and Malone 2010), and recombinant proteins (Barral et al. 2019).

To date, there is no efficient treatment for CLA since antibiotics are not able to penetrate the encapsulated granulomas formed by the host to contain the bacteria. Although some treatments based on silver nanoparticles (Santos et al. 2019) and Brazilian green propolis (Kalil et al. 2019) ointments were tested with good outcomes, the internal form of the disease remains without effective treatment. Consequently, herd vaccination, discussed above, is the best approach for CLA control and prevention.

Corynebacterium auriscanis

Corynebacterium auriscanis was first isolated from dogs presenting otitis (Collins et al. 1999). It

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