| Summary: | <i> </i><i>Ophiocordyceps</i><i> </i><i>sinensis</i> Berk. is a fungal parasite that parasitizes the larvae of Hepialidae and is used as a traditional Chinese medicine. However, it is not clear how<i> O. </i><i>sinensis</i> infects its host. The encoding gene haplotype diversity and predicted function of the nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductase (CPR) related to the fungal pathogenicity was analyzed for 219 individuals from 47 <i>O. </i><i>sinensis</i> populations. Two NADPH CPR genes of <i>O. </i><i>sinensis</i> were detected and their dominant haplotypes were widely distributed throughout the entire distribution range in Western China. Only 5.43% of all <i>O. </i><i>sinensis</i> individuals possessed the specific private haplotypes of NADPH CPR-1 and CPR-2 genes. Bioinformatic analyses predicted that the phosphorylation sites, motifs, and domains of NADPH CPR of <i>O. </i><i>sinensis</i> were different between those encoding by the dominant and private gene haplotypes. The one-to-one match fungus–host correspondence of the same individual suggested that the widely distributed <i>O. </i><i>sinensis</i> with the dominant NADPH CPR gene haplotypes may strongly infect almost all host insects through a random infection by oral or respiratory pores. Conversely, <i>O. </i><i>sinensis</i> with the specific private NADPH CPR gene haplotypes is likely to infect only a few corresponding host insects by breaching the cuticle, due to the changed NADPH CPR structure and function.
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