Mycoplasmas, the smallest bacteria lacking a cell wall, can cause various diseases in both humans and animals. Mycoplasmas harbor a variety of virulence factors that enable them to overcome numerous barriers of entry into the host; using accessory proteins, mycoplasma adhesins can bind to the receptors or extracellular matrix of the host cell. Although the host immune system can eradicate the invading mycoplasma in most cases, a few sagacious mycoplasmas employ a series of invasion and immune escape strategies to ensure their continued survival within their hosts. For instance, capsular polysaccharides are crucial for anti-phagocytosis and immunomodulation. Invasive enzymes degrade reactive oxygen species, neutrophil extracellular traps, and immunoglobulins. Biofilm formation is important for establishing a persistent infection. During proliferation, successfully surviving mycoplasmas generate numerous metabolites, including hydrogen peroxide, ammonia and hydrogen sulfide; or secrete various exotoxins, such as communityacquired respiratory distress syndrome toxin, and hemolysins; and express various pathogenic enzymes, all of which have potent toxic effects on host cells. Furthermore, some inherent components of mycoplasmas, such as lipids, membrane lipoproteins, and even mycoplasmagenerated superantigens, can exert a significant pathogenic impact on the host cells or the immune system. In this review, we describe the proposed virulence factors in the toolkit of notorious mycoplasmas to better understand the pathogenic features of these bacteria, along with their pathogenic mechanisms.

TLR4 is usually not assumed to be involved in Mycoplasma recognition. In this study we showed that the Mycoplasma pneumoniae‐derived lipids did interact with TLR4 which subsequently initiates the activation of NLRP3 inflammasome and formation of a positive feedback loop between autophagy and NF‐κB signalling cascade, ultimately promoting proinflammatory cytokines production in macrophages.

Mycoplasmas are a large group of prokaryotes which is believed to be originated from Gram-positive bacteria via degenerative evolution, and mainly capable of causing a wide range of human and animal infections. Although innate immunity and adaptive immunity play crucial roles in preventing mycoplasma infection, immune response that develops after infection fails to completely eliminate this bacterium under certain circumstances. Thus, it is reasonable to speculate that mycoplasmas employ some mechanisms to deal with coercion of host defense system. In this review, we will highlight and provide a comprehensive overview of immune evasion strategies that have emerged in mycoplasma infection, which can be divided into four aspects: (i) Molecular mimicry and antigenic variation on the surface of the bacteria to evade the immune surveillance; (ii) Overcoming the immune effector molecules assaults: Induction of detoxified enzymes to degradation of reactive oxygen species; Expression of nucleases to degrade the neutrophil extracellular traps to avoid killing by Neutrophil; Capture and cleavage of immunoglobulins to evade humoral immune response; (iii) Persistent survival: Invading into the host cell to escape the immune damage; Formation of a biofilm to establish a persistent infection; (iv) Modulation of the immune system to down-regulate the intensity of immune response. All of these features increase the probability of mycoplasma survival in the host and lead to a persistent, chronic infections. A profound understanding on the mycoplasma to subvert the immune system will help us to better understand why mycoplasma is so difficult to eradicate and ultimately provide new insights on the development of therapeutic regimens against this bacterium in future.

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