Abstract
Successful bacterial pathogens have evolved to avoid activating an innate immune system in the host that responds to the pathogen through distinct Toll-like receptors (TLRs). The general class of biochemical components that activate TLRs has been studied extensively, but less is known about how TLRs interact with the class of compounds that are still associated with the live pathogen. Accordingly, we examined the activation of surface assembled TLR 2, 4, and 5 with live Tier 1 Gram-negative pathogens that included Yersinia pestis (plague), Burkholderia mallei (glanders), Burkholderia pseudomallei (melioidosis), and Francisella tularensis (tularemia). We found that Y. pestis CO92 grown at 28°C activated TLR2 and TLR4, but at 37°C the pathogen activated primarily TLR2. Although B. mallei and B. pseudomallei are genetically related, the former microorganism activated predominately TLR4, while the latter activated predominately TLR2. The capsule of wild-type B. pseudomallei 1026b was found to mitigate the activation of TLR2 and TLR4 when compared to a capsule mutant. Live F. tularensis (Ft) Schu S4 did not activate TLR2 or 4, although the less virulent Ft LVS and F. novicida activated only TLR2. B. pseudomallei purified flagellin or flagella attached to the microorganism activated TLR5. Activation of TLR5 was abolished by an antibody to TLR5, or a mutation of fliC, or elimination of the pathogen by filtration. In conclusion, we have uncovered new properties of the Gram-negative pathogens, and their interaction with TLRs of the host. Further studies are needed to include other microorganism to extend our observations with their interaction with TLRs, and to the possibility of leading to new efforts in therapeutics against these pathogens.
Highlights
The initial interaction of a pathogen with the host is a critical time for both the pathogen and the host
After two days of incubation, Yersinia pestis (Yp) CO92 cells grown at the two different temperatures were each suspended in PBS and cell concentration adjusted before adding the live pathogen to HEK293 cells expressing TLR2 or TLR4
When Yp CO92 cells grown at 37°C were used as the inoculum, we saw an increase in activation of TLR2 with an increase in cell number; we did not see a simultaneous increase in TLR4 activation
Summary
The initial interaction of a pathogen with the host is a critical time for both the pathogen and the host. The location that TLRs are assembled by the host cell reflects the type of ligand that it might encounter during the interaction with a pathogen. For the purpose of this present report, we are focusing on only the surface assembled TLRs (see Figure 1). In the former group, TLR1 combines with TLR2 (heterodimer) to recognize triacyllipopeptides, and the heterodimer TLR2/TLR6 recognizes diacyllipopeptides (Akira et al, 2006; Kang et al, 2009; Kurokawa et al, 2012; Nakayama et al, 2012). Unlike other TLRs assembled on the surface of the cell, a subset of TLR4-MD2-LPS complexes may be recruited into an endosomal compartment to activate an alternative signal transduction pathway for the induction of proinflammatory cytokines and type I interferons (IFNs) (Kagan et al, 2008). The homodimer TLR5 is activated by the bacterial flagellin subunit, which is the major subunit of the assembled bacterial flagella (Hayashi et al, 2001; Donnelly and Steiner, 2002; Smith et al, 2003)
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