Innate Responses to Lp

Upon entering macrophages, Lg replicate. But Macrophages mount response which induce pro-inflammatory cytokines (Il-12, IL-1 B, TNF, IL-1B, chemokines). Il-12 is important important because activates NK and NKT cells to secrete IFNy which activate macrophages which eliminate Lp.

Macrophages express TLRs which can recognize microbial patterns. Lp activates Macrophages most likely through TLR2.  (Hawn, Akamine, 2005, Girard) TLR2, but not TLR4, is an important molecule for host resistance against the intracellular growth of Lp as demonstrated by the ability of the bacterium to growth within macrophages from TLR2-/- mice, whereas TLR4 deficient macrophages did not affect Lp growth.

TLR5 has recently been reported to be repsonisble for the immune response to L p through the recongition of bacterial flagellin. (Hawn)

TLR9?

MyD88 is critical: K. Takeda and S. Akira, Cellular Microbiology 2003. All these TLRs (TLR5, 7, 9, 2, 4) signal through MyD88. Cytokine production by Macrophages in response to Lp requires MyD88. But Lp grows equally as well. So no inherent suspectibility ex vivo. However, in vivo, MyD88 is required for clearance of Lp.

Elimination of a single TLR is not sufficient to confer a Lp susceptibility phynotype as strong as that obserrved for MyD88 deficient m ice. In TLR2 knockout mice, there is a defect in IL-12p40. However, TLR2 deficient mice have a slight defect in clearance of Lp. No difference in clearance from the lung was observed for mice deficient in TLR4, TLR5, or TLR9.  So probably multiple TLRs are involved in response to Lp.

Innate Responses to Lp

If deplete CD4 or CD8 more suspectible to Lp. DCs are important for this adaptive response.  (Brieland, Engleberg, Friedman, Horwitz, Kline, Marre, Skerrett, Yamamoto.

Gordon D, Bray MA, Morley J. Prostaglandins produced by activated macrophages infected with Lp inhibit T cell responses.

Genetics of Host Resistance:

Chromosome 11 involved in suspeptibility to anthrax and chlamydiaie.  Gene on Chromosome 13 which confers resistence to Lp.