Immune Evasion of Mycoplasma bovis: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Hussam Askar.

Mycoplasma bovis (M. bovis) causes various chronic inflammatory diseases, including mastitis and bronchopneumonia, in dairy and feed cattle. It has been found to suppress the host immune response during infection, leading to the development of chronic conditions.

  • Mycoplasma bovis
  • immune response
  • exhausted T-cell
  • infection
  • immune evasion

1. Introduction

Infection of dairy and feed cattle by Mycoplasma is a global issue with consequences for cattle health and economics. M. bovis is responsible for bronchopneumonia, pharyngitis, laryngitis, otitis, keratoconjunctivitis, meningitis, and mastitis, as well as hormonal diseases such as metritis, infertility, and abortion. All age groups are susceptible to M. bovis infection, and the pathogen can be shed and survive for years in contaminated herds [1]. Such diseases have substantial economic implications for the dairy and beef industries [2,3][2][3]. In the past few years, M. bovis has emerged as a significant pathogen in Europe [3], North America [4], and Japan [5], resulting in calf mortality, weight loss, and a significant drop in milk production [6]. The use of mycoplasma antibiotics is often ineffective and presents a global problem, as tetracycline- and spectinomycin-resistant bacteria are increasing in prevalence [7]. In addition, M. bovis prevents lymphocyte proliferation due to its immune-suppressive characteristics [8], and promotes bovine lymphocytic apoptosis in response to mitogens [9]. Although there have been several studies on M. bovis infections, both in vivo and in vitro, there are conflicting findings regarding whether these same processes take place during bona fide M. bovis infection. Several research assessments have revealed that M. bovis adheres to surfaces (Figure 1), is located between cells, and does not transfer intracellularly on bronchial epithelial cells [10]. Contrary to this, other studies show that M. bovis attaches to cell surfaces and migrates intracellularly into neutrophils and macrophages [11,12,13][11][12][13]; this occurs through phagocytosis via active neutrophils and macrophages. Furthermore, it can invade erythrocytes [14,15][14][15] when moving through the immune system [9]. Mycoplasma can spread systemically by invading peripheral blood mononuclear cells (PBMCs) and erythrocytes while evading immune reactions. Some studies have indicated the M. bovis-induced activation and development of different cytokines from bovine macrophages, such as IFN-γ, interleukin-4 [16], TNF-α, and nitric oxide [14]. This is not surprising, as M. bovis has been implicated by numerous studies (including those listed above) in the regulation of immune response both in vivo and in vitro [15,17][15][17]. Van der Merw et al., (2010) showed that Mycoplasma bovis strain Mb1 invades and adheres to bovine PBMCs, preventing their proliferation, but does not appear to alter developmental responses in functional cytokines such as IFN-γ. In a relatively short time, M. bovis can invade any type of PBMC, resulting in the induction of lymphocyte differentiation and spreading to any host tissue. Adhesion is the primary step of infection with mycoplasma [18]. A few recognized uncovered surface proteins have been classified as adhesins [19,20][19][20]. However, cell-dependent adhesion molecular pathways have not yet been analyzed in depth. α-Enolase, NADH oxidase (NOX), and methylenetetrahydrofolate-tRNA-(uracil-5-)-methyltransferase (TrmFO), which bind to fibronectin and plasminogen and function as the connection between the host cell receptors and bacterial adhesion, have recently been identified as adhesins [21,22,23][21][22][23] that may promote invasion and M. bovis dissemination in hosts [24]. In vivo defensive studies on the irregular intracellular positioning of M. bovis in host cells are available [12,25,26,27][12][25][26][27]. Inconsistent findings on PBMC contamination by M. bovis have been obtained regarding apoptosis induction, cytotoxic effects, and the host cells’ viability [8,28,29,30][8][28][29][30]. Similarly, Mycoplasma bovis has been found to inhibit the development of PBMCs [8,29,31,32][8][29][31][32].

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Figure 1. The production of hydrogen peroxide (H2O2) plays a crucial role in M. bovis virulence. M. bovis adheres to surfaces of bronchial epithelial cells that release various cytokines when exposed to Mycoplasma (created using BioRender.com).

Dudek et al., (2020) explored the leukocytes characterizing the host antimicrobial resistance mechanisms. Several in vitro experiments have been carried out on the effect of leukocytes on M. bovis; however, these findings are difficult to transfer to in vivo conditions. Moreover, only a few experiments have been carried out on the local immune reaction in M. bovis-induced pneumonia. Cytometry tests were carried out on an experimental calf infection model to estimate the effects of an M. bovis strain in the field on changes in the peripheral blood leukocyte reaction, including phagocytic activity and oxygen metabolism. Immunohistochemical staining has been used to assess the local lung immunity of experimentally infected calves. The general stimulation of phagocytic activity and the killing mechanism of peripheral blood leukocytes in response to M. bovis infection indicate the upregulation of cellular antimicrobial pathways. In infected lungs, local immune responses are characterized by T- and B-cell activation but with more enhanced lymphocytic T-response. The activation of local lung immunity has also been confirmed by the high expression of phagocytes and antigen-presenting cells post-infection. Stimulation does not seem to be effective in eliminating M. bovis from the host and preventing specific lung lesions, suggesting the pathogen’s ability to avoid the host immune reaction—either by peripherals or by local cells—in M. bovis-induced pneumonia [33].

2. The Immune Response to M. bovis

2.1. Humoral and Cellular Immunity

The immune response can be divided into humoral immunity and cellular immunity, with cellular immunity regulated by T-cells and B-cells regulating humoral immunity. The immune system develops cytokines, including interleukins, which balance humoral and cell-mediated immune responses. T-cells have a specific antigen (antibody)-binding receptor molecule on the cell surface, which is called a T-cell receptor (TCR). Many TCRs recognize parts of major histocompatibility complex (MHC) molecules, especially the antigenic peptides linked to those molecules. T-helper cells (Th CD4 cells) recognize processed foreign peptides on the surface of antigen-presenting cells (APCs) complexed with MHC class II molecules and induce an immune response by secreting cytokines that stimulate CD8 T-cells and B-cells. Killer or cytotoxic T-cells (CD8) participate in surface interactions with other cells carrying processed foreign peptides complexed with MHC class I molecules [13,34][13][34]. Cellular immunity also includes regulatory T-cells (Treg), which, after the immune response, suppress the development of CD8 T-cells and memory T-cells [35]. Immune response induction—both humoral and cell-mediated—depends on the activation of Th-cells and cytokines’ release [36]. In specialized antigen-presenting cells (APCs), including macrophages, dendritic cells, and B-cells, among others, antigens are recruited to process and present peptides on Th-cell class II molecules. Upon identifying the MHC class II complex, the Th-cells become activated, and their function changes to that of effector Th- and memory Th-cells [35]. The activated Th-cells secrete different cytokines, primarily IL-2, which functions autocrinally and increases the population of Th-cells. The cytokine production by Th-cells also initiates B-cells’ division into memory B-cells and the secretion of antibodies by plasma cells. T-helper cells also secrete cytokines, which drive T-cells to become memory T-cells and effector T-cells, cytotoxic T-cells that recognize and lyse modified self-cells, such as virus-infected cells recognized by the antigen supplied by MHC class I molecules [13]. It has been stated that the cellular immune response is more successful than the humoral response in the elimination of M. bovis from the host [37]. A critical event essential to the successful activation of the immune response to any infectious pathogen is the mechanism of antigen processing and presentation by MHC class I and II molecules. Both cell-mediated and humoral immune responses can be improved by vaccination to ensure that M. bovis infiltrating mucosal sites are eliminated before the onset of the disease.

2.2. Mucosal Immunity

The mucosal immune system includes digestive, gastrointestinal, urogenital, and exocrine glands. The predominant isotype formed in bovine species at mucosal sites is IgG1. The antigen-specific immune responses of Peyer’s patches dictate mucosal immune development through the production of cytokines following immune cell interactions. Since oral and transtracheal inoculation of M. bovis mainly colonized the upper respiratory tract and the tonsillar mucosa, at the autopsy, both colonized the palatine and pharyngeal tonsils with M. bovis in all inoculated calves. The tonsils of orally inoculated cattle had the largest amounts of Mycoplasma. These results confirm previous reports of naturally occurring M. bovis infection in calves indicating the initial colonization site in the upper respiratory tract [38]. Consequently, lymphoid tissue, particularly antibodies, is necessary to localize mycoplasma infections at mucosal sites of disease, preventing transfer to other tissues and arthritis production [35]. With high IL-4 levels and low levels of IFN-γ and IgG1 antibodies, the pulmonary bovine immune response to M. bovis is primarily anti-inflammatory. Simultaneously, it was found that M. bovis primarily infects the mucosal and serosal surfaces and live bacteria in infected cattle brains. Previous studies saw bacterial antigens also in the synovial membranes and infected cattle’s liver and kidneys [9]. Different strains of M. bovis reside on mucosal and extracellular surfaces but can invade and survive in various host cells. M. bovis can be seen living within the bovine alveolar macrophages. M. bovis infection in bovine epithelial cells occurs in many epithelial cell types, including embryonic bovine tracheal cells, embryonic bovine lung cells, and primary bovine mammary cells [39]. M. bovis typically produces a heavy local mucosa characterized by high serum IgG and IgA reactions. Similarly, M. bovis mammary gland inoculation results in IgG serum and local IgG and IgA serum mucosa. However, to prevent infections, systemic antibodies are critical, and serum IgG M. bovis titers are associated with arthritis defense. Local antibodies are likely to be more critical on mucosal surfaces. For example, concentrations of anti-M. bovis antibodies correlated in milk but not in serum with resistance to reinfection in cows after M. bovis mastitis. IgG concentrations bronchoalveolar lavage fluid (BAL) are linked to resistance to respiratory disease associated with M. bovis. Mycoplasma respiratory infections are commonly recognized to have significant immunopathological components, characterized by large accumulations of lymphocytes in infected tissues, cytokine output, and inflammation of the lungs [2]. Mycoplasmas, including M. bovis, may also modulate some inflammatory responses. However, in the lungs of calves with M. bovis infections, little is known about the cytokine environment. In response to the M. bovis antigen, peripheral blood mononuclear cells from M. bovis-infected calves secreted IFN-γ and IL4 and developed a strong systemic IgG1 response with little IgG2. These results suggest that M. bovis induces a mixed Th1-Th2 cytokine response, although the lack of development of IgG2 was more consistent with a Th2-biased response [2]. The strategies adopted by pathogens during infection fall into two different categories: those that alter the host immune response and those that cause the pathogens to transform themselves or their location in the host to escape the host immune response.

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