Brain Microbial Populations in HIV/AIDS: α-Proteobacteria Predominate Independent of Host Immune Status

Abstract

The brain is assumed to be a sterile organ in the absence of disease although the impact of immune disruption is uncertain in terms of brain microbial diversity or quantity. To investigate microbial diversity and quantity in the brain, the profile of infectious agents was examined in pathologically normal and abnormal brains from persons with HIV/AIDS [HIV] (n = 12), other disease controls [ODC] (n = 14) and in cerebral surgical resections for epilepsy [SURG] (n = 6). Deep sequencing of cerebral white matter-derived RNA from the HIV (n = 4) and ODC (n = 4) patients and SURG (n = 2) groups revealed bacterially-encoded 16 s RNA sequences in all brain specimens with α-proteobacteria representing over 70% of bacterial sequences while the other 30% of bacterial classes varied widely. Bacterial rRNA was detected in white matter glial cells by in situ hybridization and peptidoglycan immunoreactivity was also localized principally in glia in human brains. Analyses of amplified bacterial 16 s rRNA sequences disclosed that Proteobacteria was the principal bacterial phylum in all human brain samples with similar bacterial rRNA quantities in HIV and ODC groups despite increased host neuroimmune responses in the HIV group. Exogenous viruses including bacteriophage and human herpes viruses-4, -5 and -6 were detected variably in autopsied brains from both clinical groups. Brains from SIV- and SHIV-infected macaques displayed a profile of bacterial phyla also dominated by Proteobacteria but bacterial sequences were not detected in experimentally FIV-infected cat or RAG1−/− mouse brains. Intracerebral implantation of human brain homogenates into RAG1−/− mice revealed a preponderance of α-proteobacteria 16 s RNA sequences in the brains of recipient mice at 7 weeks post-implantation, which was abrogated by prior heat-treatment of the brain homogenate. Thus, α-proteobacteria represented the major bacterial component of the primate brain’s microbiome regardless of underlying immune status, which could be transferred into naïve hosts leading to microbial persistence in the brain.

HIV-induced immunosuppression is associated with colonization of the proximal gut by environmental bacteria

“…Clinically, our knowledge of opportunistic pathogens in relation to HIV-related proximal gut problems is rather limited, and clinical signs and symptoms alone rarely suggest a specific etiology. Besides the distal gut microbiome, high-throughput sequencing has been used to examine the effects of HIV infection on the microbiomes in the vagina [29–31], lung [32], mouth [33, 34], Semen [35], and anus [36] as well as in normally sterile body sites such as the brain [37] and blood [38, 39], but not in the proximal gut. Unlike its distal counterpart, the status of microbiome in the proximal gut in HIV infection was only examined recently by analysis of gastric juice samples from only two HIV patients [40].…”

The primate vaginal microbiome: Comparative context and implications for human health and disease

“…Eukaryotic microbes (e.g., fungi and amoebas) make up the remainder. These diverse microbial communities reside on all external surfaces of primate bodies as well as most internal tracts and passages that connect to the exterior, such as the skin, mouth, nose, gastrointestinal tract, and vagina (Table 2A), as well as regions once thought to be sterile [e.g., brain, amniotic sac (DiGiulio et al, 2008;Branton et al, 2013)]. …”

Future-Generation Sequencing and Clinical Microbiology

“…74 Where there is no culturable organism, the results are more striking. These results include some newly discovered brain infections validated through dramatic animal studies, 75 culture-negative eye infections, 76 and amniotic fluid. 77 Another key Future-Generation Sequencing application for sequencing is during asymptomatic spells in chronic infections; only information-rich methods can demonstrate conclusively that the infection has continued rather than simply recurred.…”