Corynebacterium, Arcanobacterium, and Trueperella

Corynebacterium, Arcanobacterium, and Trueperella

Thiago D. Barral, Ricardo W. Portela, Núbia Seyffert, and Robert J. Moore


The genus Corynebacterium belongs to the family Corynebacteriaceae, order Corynebacteriales, class Actinobacteria and phylum Actinobacteria (Tauch and Sandbote 2014). This genus is usually referred as a part of the CMNR group of pathogens that also includes the genera Mycobacterium, Nocardia and Rhodococcus. Corynebacterium species are Gram‐positive, non‐motile, pleomorphic (irregular or club‐shaped), non‐sporulating bacteria, with a high G + C content in the DNA. A defining characteristic is the presence of a corynomycolic acid layer that covers the bacterial cell wall, giving it a structure which may be functionally equivalent to the outer membrane of Gram‐negative bacteria (Burkovski 2018).

Corynebacterium species can be found in diverse environments and include pathogenic, non‐pathogenic, and species with biotechnological applications. Corynebacterium pseudotuberculosis, Corynebacterium diphtheriae and Corynebacterium ulcerans are the three principal species of most human and animal medical relevance, due to production of toxins such as diphtheria toxin and phospholipase D (PLD). C. pseudotuberculosis is the major species that infects animals. A summary of Corynebacterium species and their main hosts and diseases is provided in Table 32.1.

Corynebacterium pseudotuberculosis

Caseous lymphadenitis (CLA), a disease that affects sheep and goats, is the most prevalent disease caused by C. pseudotuberculosis, although this bacterium can infect horses and cattle to cause ulcerative lymphangitis. More rarely, infections have been reported in buffaloes, pigs, and humans. Two C. pseudotuberculosis biotypes are described, the ovis and the equi biovars (Songer et al. 1988). Differences have been noted between the protein expression profiles of the biovars (Silva et al. 2017). CLA is found worldwide and can cause significant economic losses due to decreases in the production of wool, milk, and meat, and reduction of the market value of leather from affected animals due to scarring (Dorella et al. 2006). There are two clinical manifestations of CLA: (i) granulomatous lesions, culminating in the necrosis of superficial lymph nodes and subcutaneous tissues, and (ii) the visceral form, resulting in lesions within internal organs and lymph nodes (Figure 32.1).

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).

Table 32.1 Main hosts and diseases caused by Corynebacterium species.

Species Host Disease
C. amycolatum Human Nosocomial endocarditis, sepsis
C. accolens Human Pelvic osteomyelitis
C. ammoniagenes Human Nappy rash
C. argentoratense Human Tonsillitis
C. aurimucosum Human Urinary tract infection
C. auriscanis Dog External otitis
C. bovis Cattle Mastitis
C. camporealensis Sheep Mastitis
C. capitovis Sheep Dermatitis
C. cystitidis Cattle Cystitis, pyelonephritis
C. diphtheriae Human Diphtheria
C. epidermidicanis Dog Pruritus
C. falsenii Human Bacteremia
C. freneyi Human Bacteremia
C. genitalium Human Urethritis
C. glucuronolyticum Human Genitourinary tract infection
C. imitans Human Pharyngeal diphtheria‐like disease
C. jeikeium Human Endocarditis
C. kroppenstedtii Human Granulomatous mastitis
C. kutscheri Mice Abscesses, pneumonia
C. lactis Dog Cutaneous abscess
C. lipophiloflavum Human Bacterial vaginosis
C. mastiditis Sheep Mastitis
C. minutissimum Human Erythrasma
C. mustelae Ferret Sepsis
C. pilosum Cattle Pyelonephritis
C. propinquum Human Respiratory tract infection
C. pseudodiphtheriticum Human Nosocomial pneumonia
C. pseudotuberculosis Sheep/goat Caseous lymphadenitis
C. renale Cattle Pyelonephritis
C. resistens Human Bacteremia
C. riegelii Human Urinary tract infection
C. sputi Human Pneumonia
C. striatum Human Endocarditis
C. suicordis Pig Pericarditis
C. tuberculostearicum Human Surgical wound infections
C. ulcerans Human Skin infection
C. ulceribovis Cattle Skin infection
C. urealyticum Human Urinary tract infection
C. ureicelerivorans Human Septicemia
C. xerosis Human/pig Nosocomial pneumonia/abscesses
Schematic illustration of examples of lesions caused by Corynebacterium pseudotuberculosis.

Figure 32.1 Examples of lesions caused by Corynebacterium pseudotuberculosis. External granulomatous lesion in a sheep, before (a), and after (b) surgical incision. Internal lesions in mice lungs (c), and liver (d) after experimental challenge with a viscerotropic strain.

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).


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.


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).

Schematic illustration of scheme of virulence factors present in Corynebacterium pseudotuberculosis.

Figure 32.2 Scheme of virulence factors present in Corynebacterium pseudotuberculosis. After the bacterium enters the host at the infection site, the exotoxin phospholipase D (PLD) damages the cells membrane and therefore facilitates bacterial spread. Once within the host, the bacterium may be phagocyted by a macrophage. The PLD plays a role in disrupting the phagosome while the protein kinase G (PknG) may be responsible for the inhibition of phagosome and lysosome fusion. The copper/zinc‐dependent superoxide dismutase (SodC) may inhibit the action of reactive oxygen species (ROS). These virulence factors facilitate the bacterial evasion of cellular clearance mechanisms, leading to cell death after intracellular multiplication with subsequent bacterial spread. Other putative virulence factors in the figure are: adherence pilus structure (SpaA, SpaB, SpaC, SpaD, SpaE and SpaF); mycolic acids that covers the bacterium cell wall (corynomycolic acids); an endo‐β‐N‐acetylglucosaminidase (CP40); and neuraminidases (NanH) that may have functions in C. pseudotuberculosis pathogenesis.


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.

Bovine Pyelonephritis Caused by Corynebacterium Species

Pyelonephritis is a renal and lower urinary tract bacterial inflammation that mostly affects cattle and is associated with infection by Corynebacterium cystitidis, Corynebacterium pilosum, and frequently Corynebacterium renale, although bacterial species such as Trueperella pyogenes, Escherichia coli, Staphylococcus aureus, and others may also be involved. Its clinical signs may include brown or red urine, anorexia or reduced appetite and weight loss, fever and colic, swishing of the tail and gross hematuria or pyuria, dilatations of kidney and ureters (Braun et al. 2008). One of the main virulence factors of C. renale may be a urease that has been hypothesized to be responsible for the kidney necrosis, due to liberation of ammonia from the urease‐catalyzed hydrolysis of urea (Jerusik et al. 1977). Risk factors such as parity, twin calving, endometritis and ketosis may be predisposing factors associated with this disease (Solomon et al. 2020).

It has been shown that C. cystitidis, C. pilosum, and C. renale adhere to bovine urinary bladder epithelium by attaching to the most aged cells first (Sato et al. 1982), and this adhesion is mediated by the pili structure, but its cellular receptors are not well understood and could have an increasing age‐related factor. These species have long survival periods in soil. C. renale, C. cystitidis, and C. pilosum survived for 56, 63, and 210 days in the environment, respectively, and the cycle of infection was suggested to include bacteria shed in the urine from infected cows that contaminate the soil; bacteria survives in the soil for a considerable period of time, and attachment to the epithelial cells of the vulva of uninfected cows, followed by a retrograde infection, may result in pyelonephritis (Hayashi et al. 1985).

Because of ease of control of infection by treatment with penicillin G, there has been minimal investigation of its pathogenesis in recent decades.

Other Animal Pathogenic Corynebacterium Species

Corynebacterium auriscanis

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

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Nov 13, 2022 | Posted by in GENERAL | Comments Off on Corynebacterium, Arcanobacterium, and Trueperella

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