Abstract
The two-component response regulator Rrp2 is a key activator controlling the production of numerous virulence factors of Borrelia burgdorferi, the Lyme disease pathogen. Previously it was shown that the cognate histidine kinase HK2 is not required for Rrp2 activation in vitro, nor for mammalian infection upon needle inoculation, raising the question whether HK2 has any role in the enzootic cycle of B. burgdorferi. In this study, we demonstrated that HK2 is not required for spirochetal survival in the tick vector. When fed on naive mice, the hk2 mutant had reduced infectivity through the route of tick bite, suggesting that the spirochetes lacking HK2 had a disadvantage in the enzootic cycle. Furthermore, overexpression of hk2 reduced the level of Rrp2 phosphorylation, suggesting that HK2 can function as a phosphatase to dephosphorylate Rrp2. Strains overexpressing hk2 impaired the expression of RpoN regulon whose activation is dependent on Rrp2 phosphorylation and activation, and had reduced infectivity in mice. Taken together, these results demonstrate that although HK2 does not play an essential role in Rrp2 activation, it is important for the optimal fitness of B. burgdorferi in the enzootic cycle.
Highlights
The Lyme disease pathogen, Borrelia burgdorferi, B. afzelii, and B. garinii, is maintained in nature in two drastic different hosts, an Ixodes tick and a mammalian host
To examine whether HK2 plays a role in tick phase of the enzootic cycle, naive Ixodes scapularis larvae were fed on immunocompetent C3H/HeN mice that were needle-infected with wild-type or the hk2 mutant spirochetes
The result showed that there was no significant difference in spirochetal numbers in the tick midguts at 48 h during feeding or after feeding on mice infected with wildtype and the hk2 mutant B. burgdorferi, suggesting that HK2 is not required for spirochetal survival during tick feeding (Figures 1A,B)
Summary
The Lyme disease pathogen, Borrelia burgdorferi, B. afzelii, and B. garinii, is maintained in nature in two drastic different hosts, an Ixodes tick and a mammalian host. Comparing to free living bacteria such as Escherichia coli, which has more than 30 two-component signal transduction systems (TCSs), B. burgdorferi has reduced to two sets of TCS, HK1/Rrp and HK2/Rrp (in addition to the chemotactic CheA-CheY system) and has evolved to employ these two TCSs to survive in each of the two hosts encountered in the enzootic cycle. HK1/Rrp, a c-di-GMP producing system, controls spirochete’s adaptation to the tick vector [1,2,3,4,5,6,7], whereas HK2/Rrp is essential for B. burgdorferi to establish infection in the mammalian host [8,9,10,11]. Rrp is a member of NtrC family transcriptional activator. It contains three putative functional domains: an N-terminal response regulator receiver
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