Neisseria infection of rhesus macaques as a model to study colonization, transmission, persistence, and horizontal gene transfer

Abstract

The strict tropism of many pathogens for man hampers the development of animal models that recapitulate important microbehost interactions. We developed a rhesus macaque model for studying Neisseria-host interactions using Neisseria species indigenous to the animal. We report that Neisseria are common inhabitants of the rhesus macaque. Neisseria isolated from the rhesus macaque recolonize animals after laboratory passage, persist in the animals for at least 72 d, and are transmitted between animals. Neisseria are naturally competent and acquire genetic markers from each other in vivo, in the absence of selection, within 44 d after colonization. Neisseria macacae encodes orthologs of known or presumed virulence factors of human-adapted Neisseria, as well as current or candidate vaccine antigens. We conclude that the rhesus macaque model will allow studies of the molecular mechanisms of Neisseria colonization, transmission, persistence, and horizontal gene transfer. The model can potentially be developed further for preclinical testing of vaccine candidates.commensal Neisseria | nonhuman primate model | type IV pili M icrobe-host interactions are often refractory to investigation because of the exquisite tropism of many bacteria for the human host. Host-restriction has prevented the development of animal models that recapitulate colonization, transmission, and persistence; hampered studies of horizontal gene transfer (HGT); and prevented preclinical testing of vaccine candidates. One means to circumvent host restrictions is to develop an animal model of infection using a related species indigenous to that animal. For example, infections by human pathogens, such as Bordetella pertussis and Chlamydia trachomatis, have been effectively modeled in animals with Bordetella bronchiseptica and Chlamydia muridarum, respectively (1, 2).The genus Neisseria and the rhesus macaque provide us with this opportunity. Neisseria are Gram-negative, diplococcal β-Proteobacteria. This genus includes >10 human-adapted species, two of which are pathogens, and an unknown number of species that naturally colonize animals. These species are highly related: >40% of the genes in pathogenic species are also present in commensals, and many of these encode virulence genes and antibiotic resistance alleles. The species are naturally competent and transfer genetic information to each other in vitro (3, 4). HGT is widely assumed to play an important role in the spread of antibiotic resistance among pathogenic Neisseria; however, there is little information on the extent to which HGT occurs in vivo.Pathogens Neisseria meningitidis and Neisseria gonorrhoeae have an exquisite tropism for man. These pathogens do not naturally infect animals; inoculated into nonhuman hosts, the pathogens will colonize only for brief periods (5, 6). Neisseria species have been isolated from a number of animals (7-10), suggesting it may be possible to develop a model for studying Neisseria-host interactions in which there are no host-restriction barriers to overcome.The ...

Heterogeneity in Rhesus Macaque Complement Factor H Binding to Meningococcal Factor H Binding Protein (FHbp) Informs Selection of Primates To Assess Immunogenicity of FHbp-Based Vaccines

“…A recent study found that rhesus macaques can be colonized naturally by Neisseria species and demonstrated the feasibility of using the macaque model to investigate colonization and transmission of the organism (30). The results of the present study indicate that the macaque model also has the potential for investigation of the effects of FH binding on the immunogenicity and safety of meningococcal FHbp vaccines.…”

Non-pathogenic Neisseria: members of an abundant, multi-habitat, diverse genus

“…The habitats of commensal Neisseria in mammals are similar to those in humans, probably due to the shared anatomical and physiological features. For example in non-human primates, the oral and nasopharyngeal microbiome has been most extensively studied in the rhesus macaque (Macaca mulatta) given its potential as an animal model for human-specific pathogens such as N. meningitidis (Weyand et al, 2013). Although Neisseria species were identified in all rhesus macaque studies, their prevalence appeared to be lower than that in humans.…”

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

“…Due to the absence of bacteremia, it was suggested that N. meningitidis may travel from the nasal cavity to the meninges and subarachnoid space via the olfactory nerves (324). In rhesus macaques, commensal neisseria bacteria (RM Neisseria) were shown to be transmitted between animals and naturally colonized the epithelium covering the cribriform plate (336), suggesting that migration of neisseria bacteria along the olfactory pathway is not a phenomenon that is observed only in animals experimentally inoculated with pathogenic N. meningitidis. In the African "meningitis belt," the onset of meningococcal meningitis epidemics coincides with harsh, dry harmattan winds.…”