Abstract

Leptospirosis can affect humans and a broad range of domestic and wild animals,¹ including the California sea lion, Zalophus californianus, which experiences outbreaks of leptospirosis periodically,^2,3,4 often with high mortality due to renal failure⁵. Understanding the genetic factors that influence resistance or susceptibility to pathogens, such as Leptospira spp., which can impact the viability of natural populations, is a key aspect of molecular epidemiology. The California sea lion MHC class II DRB (hereafter, Zaca-DRB) exhibits an unusual way of generating diversity, namely, it generates multiple functional copies that have limited polymorphism among them.⁶ We examined associations between the Zaca-DRB configuration and diversity, and leptospirosis in 77 adult sea lions with clinical and serological evidence of infection, and 28 adult sea lions that showed no clinical evidence of leptospirosis or any other infectious disease. As Zaca-DRB sequences are known to be compatible with antigen presentation of bacteria and other extracellular pathogens,⁶ we predicted that they would play a role in determining responses to these pathogenic spirochaetes. In order to account for neutral genetic variation, we genotyped the sea lions at 14 non-linked microsatellite markers. We built a series of independent generalized linear models, and logistic models to address our predictions. The models showed that the serum collected from diseased sea lions that had more Zaca-DRB genes was able to react against a wider array of serovars in in vitro detection assays and specific genes were associated to reactions against particular serovars. However, infected sea lions that had higher numbers of Zaca-DRB genes were more likely to die than those with lower diversity, and sea lions with Zaca-DRB.C or -G genes were 5 times more likely to die from leptospirosis than sea lions with other Zaca-DRB genes. It is possible that when challenged by the infective leptospires, a disadvantage of having a wider range of antigen presentation might be immunopathology. These results evidence that host-pathogen relationships are complex and that pathogen-driven selection on genes involved in the immune response, such as the MHC, is likely to reflect such complexity. To the best of our knowledge, this is the first attempt to examine the relevance of MHC class II diversity for antigen detection and disease severity following natural exposure of a marine mammal to infective leptospires.

Acknowledgements

The authors wish to thank staff at the Marine Mammal Center for their help with sample collection. Any use of trade, firm or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government.

* Presenting author

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