Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response

Abstract

At mammalian body temperature, the plague bacillus Yersinia pestis synthesizes lipopolysaccharide (LPS)-lipid A with poor Toll-like receptor 4 (TLR4)-stimulating activity. To address the effect of weak TLR4 stimulation on virulence, we modified Y. pestis to produce a potent TLR4-stimulating LPS. Modified Y. pestis was completely avirulent after subcutaneous infection even at high challenge doses. Resistance to disease required TLR4, the adaptor protein MyD88 and coreceptor MD-2 and was considerably enhanced by CD14 and the adaptor Mal. Both innate and adaptive responses were required for sterilizing immunity against the modified strain, and convalescent mice were protected from both subcutaneous and respiratory challenge with wild-type Y. pestis. Despite the presence of other established immune evasion mechanisms, the modified Y. pestis was unable to cause systemic disease, demonstrating that the ability to evade the LPS-induced inflammatory response is critical for Y. pestis virulence. Evading TLR4 activation by lipid A alteration may contribute to the virulence of various Gram-negative bacteria.

LPS remodeling is an evolved survival strategy for bacteria

“…Specifically, increased acylation of lipid A at lower temperatures may protect the bacteria from conditions in the flea digestive tract or external environment, whereas decreased acylation allows the bacteria to evade detection by the host innate immune system. Induction of the innate immune system by modifying the tetraacylated lipid A structure by overexpression of the late acyltransferase, LpxL in Y. pestis results in a complete loss of virulence (13). In contrast, it has been demonstrated that Francisella expresses a unique tetraacylated LPS (14,15) that fails to activate Toll-like receptor 4 (TLR4) at all growth temperatures due to the lack of the 1-position phosphate moiety and the length and position of the acyl groups attached to the diglucosamine backbone, enabling this Gram-negative organism to evade host detection (16).…”

Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

“…In this regard, the FimCDE mutants are stronger inducers of NF-κB activation in vitro than both wild-type and FimA-deficient P. gingivalis . In general, increased microbial immunostimulatory potential correlates with reduced microbial survival in the host, as exemplified by genetically modified Yersenia pestis expressing an immunostimulatory version of LPS (Montminy et al, 2006). It is uncertain at the moment why FimCDE-deficient mutants are more proinflammatory than wild-type P. gingivalis.…”

MD-2–Dependent Pulmonary Immune Responses to Inhaled Lipooligosaccharides

“…Differences in the potency of hexa-, tetra-, and pentaacylated endotoxins reflect differences in the ability of endotoxin-bound MD-2 to induce activation of TLR4 (17,19). On the basis of these observations, it has been suggested that the elaboration of underacylated endotoxins by Pseudomonas aeruginosa early in the evolution of pulmonary infection in cystic fibrosis (15,20,21) and by Yersinia pestis in pneumonic plague (22) contributes greatly to the virulence of these airway bacterial pathogens by blunting early host inflammatory responses needed for efficient mobilization of host defenses. However, the ability of the mammalian airway to mount graded responses to administered endotoxin, depending on endotoxin lipid A properties, and the role of MD-2 in airway responses to endotoxin have not yet been directly tested.…”