Studies of Neisseria musculi Type IV Pilus and Capsule Using the Natural Mouse Model of Colonization and Persistence

Abstract

The Neisseriaceae family is a group of Gram-negative bacteria that forms part of the microbiota of humans and animals. Within the genus Neisseria, there are only two pathogens, N. gonorrhoeae and N. meningitidis (Nme) which infect only humans and cause disease. Others are either commensals of humans or animals including wild mice, dogs, cats, cows, and non-human primates. Pathogenic Neisseria also behave like commensals in that they are able to colonize the mucosal surfaces asymptomatically. Commensal Neisseria are little studied and there is no small animal model for studying commensal Neisseria-host interactions in a natural setting. There are small animal models for studying pathogenic Neisseria infection, but due to their strict tropism for humans, they are heterologous systems which require treatment of hormones, antibiotics, and invasive procedures. Recent work in the So laboratory has circumvented the tropism issue. Former postdoctoral researcher Nate Weyand isolated Neisseria musculi (Nmus) from wild mice, and showed Nmus is genetically related to human Neisseria – including genes encoding many host interaction factors such as Type IV pilus and capsule. I expanded this study and my investigations showed that Nmus colonize laboratory mice. This work, described in chapter 2, led to a natural mouse model that now allows studies on asymptomatic colonization from the standpoint of the bacterium and the host. Using the natural mouse model of commensal Neisseria colorization and persistence, I showed that host genetics, host immune status, and bacterial host interaction factors are essential determinants for Neisseria colonization and persistence. Type IV pilus fiber and Type IV pilus retraction null mutants are defective in establishing colonization. This natural mouse model of commensal Neisseria colonization and persistence will allow us to identify new neisserial and host genes that are important for asymptomatic colonization and/ or persistence. I also showed that Nmus expresses capsule, which was a unique trait of invasive Nme, and capsule influences biofilm formation. Analyzing the capsule biosynthesis locus of Nmus, I identified additional transcriptional regulatory motifs suggesting that the mechanisms in controlling capsule production between Nmus and Nme might be different. With the recent discovery of capsule biosynthesis genes among human and animal commensal Neisseria, the dogma of capsule being a unique trait of invasive Nme is no longer valid. The expression of capsule locus by commensal Neisseria allows investigators to study the transcriptional and functional similarities and/or differences between commensal and pathogenic capsules as well as the potential impact(s) of capsules shared by the pathogenic and commensal Neisseria.