Cnes2bRegulates Host Resistance, Inflammatory Responses and Tissue Damage FollowingCryptococcus deneoformansInfection

The 32.1 Mb Cnes2 chromosome 17 interval was shown to confer resistance to progressive Cryptococcus deneoformans 52D infection. To refine the location of Cnes2 host resistance genes, a subcongenic mouse strain (B6.CBA- Cnes2b ) that contains 8.7 Mb from the telomeric region of Cnes2 was created. At 28 days postinfection B6.CBA- Cnes2b mice had a lower lung fungal burden, increased lung injury, as well as mortality compared to C57BL/6N. B6.CBA- Cnes2b mice had increased pulmonary production of pro-inflammatory mediators, chemokines and Th1-type cytokines as well as increased recruitment of monocytes and neutrophils to the lungs. Cnes2b also regulated several elements of the host response to C. deneoformans 52D infection in a sex-dependent manner. Specifically, male B6.CBA- Cnes2b mice had a lower lung fungal burden, increased brain injury and mortality relative to females. Taken together these findings demonstrate that Cnes2b regulates host inflammation in a manner that controls fungal burden and increases tissue damage. Precise identification of the genes encoded by Cnes2b could reveal key mechanisms of cryptococcal host resistance and immune reconstitution or postinfectious inflammatory syndromes. Importance The 32.1 Mb Cnes2 congenic interval from chromosome 17 of resistant CBA/J mice regulates host resistance to C. deneoformans 52D infection. This study characterizes the host response of B6.CBA- Cnes2b mice that carry an 8.7 Mb sub-congenic interval derived from Cnes2 following C. deneoformans 52D infection. B6.CBA- Cnes2b mice had reduced lung fungal burden, increased lung and brain injury, and mortality. The effects of Cnes2b differed between male and female subcongenic mice and are consistent with known sex differences in human cryptococcal disease. The host response of B6.CBA- Cnes2b mice reflects a crucial balance between effective control of fungal burden and potentially deleterious consequences of enhanced inflammation during cryptococcal infection as predicted by the damage response framework. Further analysis of the Cnes2b sub-congenic interval will lead to definitive identification of genes that confer resistance to progressive cryptococcal infection and/or contribute to deleterious inflammatory responses. Defining key mechanisms that regulate the immune response to Cryptococcus sp. is an important step towards the development of host-directed therapeutics that could improve disease outcomes.