Gut microbes, ageing & organ function:a chameleon in modern biology?

All species, including humans, are cohabited by a myriad of microbial species, which massively influences body function in a diet-, exercise- and age-dependent manner. The microbiome composition differs between individuals, partly due to the polymorphic immune system, as well as the environment, making the microbe-host interplay unique in each one of us. Ageing is a gradual loss of function in part due to reduced repair mechanisms and accumulation of tissue damage through mechanisms largely unknown. Accumulating evidence suggests that our indigenous microbes, a known major regulator of human physiology, are also connected to regulate the ageing process through signalling pathways and metabolites though the biological mechanisms are unknown. At an ageing meeting in Singapore in 2018, investigators discussed the current understanding of microbe regulation and its impact on healthy ageing. This review summarizes the highlights from the meeting and conveys some of the new ideas that emerged around gut microbes and the biology of ageing. While highly speculative, an idea emerged in which gut microbes constantly respond and evolve to environmental cues, as part of an ageing process, thus serving as a second messenger to support and attenuate organ decline in a diet-, gender- and age-dependent manner

The Lentiviral Integrase Binding Protein LEDGF/p75 and HIV-1 Replication

Retroviral replication proceeds through a stable proviral DNA intermediate, and numerous host cell factors have been implicated in its formation. In particular, recent results have highlighted an important role for the integrase-interactor lens epithelium-derived growth factor (LEDGF)/p75 in lentiviral integration. Cells engineered to over-express fragments of LEDGF/p75 containing its integrase-binding domain but lacking determinants essential for chromatin association are refractory to HIV-1 infection. Furthermore, both the levels of HIV-1 integration and the genomic distribution of the resultant proviruses are significantly perturbed in cells devoid of endogenous LEDGF/p75 protein. A strong bias towards integration along transcription units is a characteristic feature of lentiviruses. In the absence of LEDGF/p75, HIV-1 in large part loses that preference, displaying concomitant integration surges in the vicinities of CpG islands and gene promoter regions, elements naturally targeted by other types of retroviruses. Together, these findings highlight that LEDGF/p75 is an important albeit not strictly essential cofactor of lentiviral DNA integration, and solidify a role for chromatin-associated LEDGF/p75 as a receptor for lentiviral preintegration complexes. By now one of the best characterized virus–host interactions, the integrase-LEDGF/p75 interface opens a range of opportunities for lentiviral vector targeting for gene therapy applications as well as for the development of novel classes of antiretroviral drugs

Congenital Viral Infections of the Brain: Lessons Learned from Lymphocytic Choriomeningitis Virus in the Neonatal Rat

The fetal brain is highly vulnerable to teratogens, including many infectious agents. As a consequence of prenatal infection, many children suffer severe and permanent brain injury and dysfunction. Because most animal models of congenital brain infection do not strongly mirror human disease, the models are highly limited in their abilities to shed light on the pathogenesis of these diseases. The animal model for congenital lymphocytic choriomeningitis virus (LCMV) infection, however, does not suffer from this limitation. LCMV is a well-known human pathogen. When the infection occurs during pregnancy, the virus can infect the fetus, and the developing brain is particularly vulnerable. Children with congenital LCMV infection often have substantial neurological deficits. The neonatal rat inoculated with LCMV is a superb model system of human congenital LCMV infection. Virtually all of the neuropathologic changes observed in humans congenitally infected with LCMV, including microencephaly, encephalomalacia, chorioretinitis, porencephalic cysts, neuronal migration disturbances, periventricular infection, and cerebellar hypoplasia, are reproduced in the rat model. Within the developing rat brain, LCMV selectively targets mitotically active neuronal precursors. Thus, the targets of infection and sites of pathology depend on host age at the time of infection. The rat model has further shown that the pathogenic changes induced by LCMV infection are both virus-mediated and immune-mediated. Furthermore, different brain regions simultaneously infected with LCMV can undergo widely different pathologic changes, reflecting different brain region–virus–immune system interactions. Because the neonatal rat inoculated with LCMV so faithfully reproduces the diverse neuropathology observed in the human counterpart, the rat model system is a highly valuable tool for the study of congenital LCMV infection and of all prenatal brain infections In addition, because LCMV induces delayed-onset neuronal loss after the virus has been cleared, the neonatal rat infected with LCMV may be an excellent model system to study neurodegenerative or psychiatric diseases whose etiologies are hypothesized to be virus-induced, such as autism, schizophrenia, and temporal lobe epilepsy

Exploiting Amoeboid and Non-Vertebrate Animal Model Systems to Study the Virulence of Human Pathogenic Fungi

Experiments with insects, protozoa, nematodes, and slime molds have recently come to the forefront in the study of host–fungal interactions. Many of the virulence factors required for pathogenicity in mammals are also important for fungal survival during interactions with non-vertebrate hosts, suggesting that fungal virulence may have evolved, and been maintained, as a countermeasure to environmental predation by amoebae and nematodes and other small non-vertebrates that feed on microorganisms. Host innate immune responses are also broadly conserved across many phyla. The study of the interaction between invertebrate model hosts and pathogenic fungi therefore provides insights into the mechanisms underlying pathogen virulence and host immunity, and complements the use of mammalian models by enabling whole-animal high throughput infection assays. This review aims to assist researchers in identifying appropriate invertebrate systems for the study of particular aspects of fungal pathogenesis

Chemical signaling in the gastrointestinal tract

Chemical signaling via the production of small molecules such as hormones has been studied in detail in higher organisms. These molecules have important functions in maintaining physiological homeostasis as well as allowing organisms to respond to external insults. Virtually every living cell produces hormone-like diffusible small molecules that can be used to convey messages to neighboring cells—a vital step in adaptation, development, and survival within populations. Although most of our knowledge on cellular chemical communication comes from studies of multicellular eukaryotes, it is now understood that bacteria can also communicate using sophisticated signaling systems, in a way analogous to those used by higher organisms. Many of these microbes live in close association with higher eukaryotes, in mutualistic or commensal relationships. We suggest that there may be a wealth of unidentified bioactive small molecules in the human body, originating from both microbial and human cells and that have important biological functions. Because chemical signaling has important roles for the biology of both microbes and humans, detecting, identifying, and studying these chemical signals can further our understanding of the chemical interplay between microbiota and their hosts and provide us with an unexplored source of molecules that could be used for human benefit

The Salmonella enterica PhoP Directly Activates the Horizontally Acquired SPI-2 Gene sseL and Is Functionally Different from a S. bongori Ortholog

To establish a successful infection within the host, a pathogen must closely regulate multiple virulence traits to ensure their accurate temporal and spatial expression. As a highly adapted intracellular pathogen, Salmonella enterica has acquired during its evolution various virulence genes via numerous lateral transfer events, including the acquisition of the Salmonella Pathogenicity Island 2 (SPI-2) and its associated effectors. Beneficial use of horizontally acquired genes requires that their expression is effectively coordinated with the already existing virulence programs and the regulatory set-up in the bacterium. As an example for such a mechanism, we show here that the ancestral PhoPQ system of Salmonella enterica is able to regulate directly the SPI-2 effector gene sseL (encoding a secreted deubiquitinase) in an SsrB-independent manner and that PhoP plays a part in a feed-forward regulatory loop, which fine-tunes the cellular level of SseL. Additionally, we demonstrate the presence of conserved cis regulatory elements in the promoter region of sseL and show direct binding of purified PhoP to this region. Interestingly, in contrast to the S. enterica PhoP, an ortholog regulator from a S. bongori SARC 12 strain was found to be impaired in promoting transcription of sseL and other genes from the PhoP regulon. These findings have led to the identification of a previously uncharacterized residue in the DNA-binding domain of PhoP, which is required for the transcriptional activation of PhoP regulated genes in Salmonella spp. Collectively our data demonstrate an interesting interface between the acquired SsrB regulon and the ancestral PhoPQ regulatory circuit, provide novel insights into the function of PhoP, and highlight a mechanism of regulatory integration of horizontally acquired genes into the virulence network of Salmonella enterica