Previous studies demonstrated that
Leptospira biflexa
, a saprophytic species, triggers innate immune responses in the host during early infection. This raised the question of whether these responses could suppress a subsequent challenge with pathogenic
Leptospira
. We inoculated male C3H/HeJ mice with a single or a double dose of
L. biflexa
before challenge with a pathogenic serovar,
L. interrogans
ser. Copenhageni FioCruz (LIC). Pre-challenge exposure to
L. biflexa
did not prevent LIC dissemination and colonization of the kidney. However, it rescued weight loss and mouse survival thereby mitigating disease severity. Unexpectedly, there was correlation between rescue of overall health (weight gain, higher survival, lower kidney fibrosis) and higher shedding of LIC in urine. This stood in stark contrast to the
L. biflexa
unexposed LIC challenged control. Immune responses were dominated by increased frequency of B cells and effector T helper (CD4+) cells in spleen, as well as significant increases in serologic IgG2a. Our findings suggest that exposure to live saprophytic
Leptospira
primes the host to develop Th1 biased immune responses that prevent severe disease induced by a subsequent challenge with a pathogenic species. Thus, hosts exposed to live saprophytic
Leptospira
before challenge with a pathogenic serovar may withstand LIC infection with far better outcomes. Furthermore, a status of homeostasis may have been reached after kidney colonization that helps LIC complete its enzootic cycle.Previous evidence of host innate immunity induced by live saprophytic
Leptospira
led us to posit that these responses might mitigate leptospirosis severity upon a subsequent challenge with a pathogenic serovar. In this study, we validated our hypothesis. This is important for development of novel strategies to control leptospirosis and for understanding the epidemiologic risk factors of this and other infectious diseases transmitted by direct contact between pathogen and host. Unexpectedly, these studies also show that there is a correlation between kidney health after
L. interrogans
infection (less fibrosis) and higher shedding of this spirochete in urine. This suggests that a status of homeostasis may be reached after kidney colonization by
L. interrogans
that helps the spirochete fulfill its enzootic cycle.