Humanized TLR4 immunocompetent mice are more susceptible to kidney disease after infection with Leptospira interrogans than wild-type mice

Toll-Like Receptor (TLR) 4 plays a central role in the control of leptospirosis and TLR4 deficiency results in lethal infection in mice. Human TLR4 however does not recognize Leptospira spp which may allow for their escape from immune recognition. We hypothesized that the replacement of murine TLR4 with human TLR4 may produce an immunocompetent mouse model of sublethal leptospirosis. We infected TLR4/MD-2 humanized transgenic mice (huTLR4) developed on a C57BL/6J TLR4/MD-2 double knock-out background with a sublethal dose of L. interrogans serovar Copenhageni (Leptospira). We found that Leptospira disseminated to target organs of huTLR4 mice as shown by the presence of spirochetes in blood, urine and kidney after infection. We did a comparative study between huTLR4 mice and wildtype C57BL/6J (muTLR4) to find out if the differences observed in the humanized TLR4 transgenic model were due to the transgene modification or to other factors. Replacing murine TLR4 with human TLR4 resulted in considerable higher shedding of Leptospira in urine in huTLR4 mice. Regarding inflammation of the kidney, MIP-2 and iNOS were significantly decreased in huTLR4 in comparison to muTLR4, whereas TNF-α and IFN-γ were increased, but there was no difference in RANTES that was increased in both groups of infected mice. In conclusion, our data suggests that human TLR4 may mediate higher susceptibility to leptospirosis that results in kidney pathology associated with downregulation of local MIP-2, antimicrobial iNOS and RANTES which are insuficient to restrict Leptospira and reduce shedding in urine. The TLR4 humanized mouse model of sublethal leptospirosis described is a novel tool to test therapies and vaccines against this neglected re-emerging zoonotic disease.