Involvement of CD14, Toll-Like Receptors 2 and 4, and MyD88 in the Host Response to the Fungal Pathogen Cryptococcus neoformans In Vivo

LE Yauch, MK Mansour, S Shoham… - Infection and …, 2004 - Am Soc Microbiol
LE Yauch, MK Mansour, S Shoham, JB Rottman, SM Levitz
Infection and immunity, 2004Am Soc Microbiol
The major capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan
(GXM), is recognized by Toll-like receptor 2 (TLR2), TLR4, and CD14. In these studies, mice
deficient in CD14, TLR2, TLR4, and the TLR-associated adaptor protein, MyD88, were
utilized to investigate the contribution of TLRs and CD14 to in vivo host defenses against C.
neoformans. MyD88−/− mice had significantly reduced survival compared with wild-type
C57BL/6 mice after intranasal (in) and intravenous (iv) infection with live C. neoformans …
Abstract
The major capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), is recognized by Toll-like receptor 2 (TLR2), TLR4, and CD14. In these studies, mice deficient in CD14, TLR2, TLR4, and the TLR-associated adaptor protein, MyD88, were utilized to investigate the contribution of TLRs and CD14 to in vivo host defenses against C. neoformans. MyD88−/− mice had significantly reduced survival compared with wild-type C57BL/6 mice after intranasal (i.n.) and intravenous (i.v.) infection with live C. neoformans. CD14−/− mice had reduced survival when infected i.v., while TLR2−/− mice died significantly earlier after i.n. infection. Mortality was similar comparing TLR4 mutant C3H/HeJ mice and control C3H/HeOuJ mice following i.v. or i.n. challenge with C. neoformans. The course of pulmonary cryptococcosis was studied in more detail in the CD14−/−, TLR2−/−, and MyD88−/− mice. MyD88−/− mice infected i.n. had higher numbers of CFU in the lungs as well as higher GXM levels in the sera and lungs 7 days after infection than wild-type mice did. Surprisingly, there were no major differences in the levels of tumor necrosis factor alpha, interleukin-4 (IL-4), IL-10, IL-12p70, or gamma interferon in the lungs of C. neoformans-infected knockout mice compared with wild-type mice. Histopathologic analysis of the lungs on day 7 postinfection revealed minimal inflammation in all mouse groups. These studies demonstrate a major role for MyD88 and relatively minor roles for CD14 and TLR2 in the response to cryptococcal infection, with the decreased survival of MyD88−/− mice correlating with increased numbers of lung CFU and serum and lung GXM levels.
American Society for Microbiology