The role of gut bacteria in complications of heart inflammation has previously not been fully understood. Gil-Cruz et al. (2019) demonstrate a commensal Bacteroides species that triggers a cross-immune response against a bacterial protein and heart epitope, causing cardiomyopathy. This study links commensal bacteria with heart inflammation mechanistically in mice and correlatively in patients.

Despite decades of study, the molecular basis for granuloma formation and restriction of chronic pathogens remains murky. Three articles reveal how Salmonella rewires macrophage polarization (Panagi et al. and Gibbs et al.) to shift the balance between M1 and M2 granuloma macrophages and resist TNF-mediated clearance (Pham et al.).

Bacteroides genomes encode a large repertoire of proteins dedicated to the utilization of diverse plant polysaccharides and host glycans. In this issue of Cell Host & Microbe, Glowacki et al. (2020) show that B. thetaiotaomicron can also extract the monosaccharide ribose from nucleosides and characterize proteins necessary for its utilization.

In this issue of Cell Host & Microbe, Hancock et al., 2020 show that latent HCMV infection, and specifically miR-US5-2, induces TGF-β secretion, which inhibits myelopoiesis in uninfected HPCs. They also show that HCMV-infected cells become resistant to TGF-β signaling through targeting of SMAD3 by miR-UL22-A-3p and -5p.

The neonatal gut microbiome undergoes dynamic changes in response to many nutritional and environmental variables. A recent study by Singer et al. in Nature Medicine elucidates several mechanisms to inhibit the expansion of gut-derived pathobionts in a dysbiotic neonatal gut and prevent these pathobionts from disseminating systemically and causing sepsis in neonatal mice.

Humoral immunity is an essential component of the protective immune response to flavivirus infection. Typically, primary infection generates a robust neutralizing antibody response that mediates viral control and protection. It is becoming increasingly apparent that secondary infection with a closely related flavivirus strain can result in immunological cross-reactivity; however, the consequences to infection outcome remain controversial. Since its introduction to Brazil in 2015, Zika virus (ZIKV) has caused an epidemic of fetal congenital malformations within the Americas. Because ZIKV is a mosquito-borne flavivirus with a high degree of sequence and structural homology to Dengue virus (DENV), the role of immunological cross-reactivity in ZIKV and DENV infections has become a great concern. In this review, we highlight contemporary findings that implicate a role for flavivirus antibodies in mediating protection, contributing to pathogenesis, and seeding the human placenta.

Proviral latency is a major barrier to a cure for HIV. In this issue of Cell Host & Microbe, Hataye et al. (2019) show that reactivation of HIV latency is a non-deterministic, highly stochastic (i.e., noisy) process and propose that stochastic transitions to exponential viral expansion require a critical threshold of virus.

At birth, microbes rapidly colonize our epithelial surfaces. In this issue of Cell Host & Microbe, Leech et al. (2019) uncover how the neonatal immune system discriminates between a colonizing commensal and pathogen to selectively generate tolerance to commensal species.

Plants remember information related to previous pathogen infection as immunological memory, leading to a primed state of enhanced immune responses. In this issue of Cell Host & Microbe, Gong et al. (2019) discover that immune priming is established through crosstalk between cell-surface co-receptors upon MAMP perception.

Bacterial pathogens secrete effector proteins to manipulate host signaling proteins and cellular structures. In this issue of Cell Host & Microbe, Pagliuso et al. (2019) propose an effector mechanism in Listeria monocytogenes whereby an RNA-binding protein associates with bacterial RNA that stimulates RIG-I (retinoic acid inducible gene I)-based innate immunity in the host cytosol.

Gilchuk et al. (2019) and Zhu et al. (2019) provide detailed structural information about epitopes on influenza virus N9 neuraminidase and characterize breadth, potency, mechanism of action, and in vivo protective effects of human antibodies targeting these epitopes. The findings highlight the importance of neuraminidase as a target for improved influenza virus vaccines.

All life forms rely on defenses to fight off viruses that prey on them. Intriguingly, bacteria often develop the blueprints for these. Recently published in Nature, Cohen et al. (2019) uncover a widespread bacterial anti-viral defense system, which may be the evolutionary precursor to the metazoan cGAS-STING immune pathway.

Intestinal pathogens encounter the microbiota as they seek their host target, potentially impacting the infection. In a recent Cell paper, Shi et al. (2019) show that unique segmented filamentous bacteria prevent rotavirus from infecting the intestinal epithelium. Proposed mechanisms include direct effects on the virus and stimulation of epithelial proliferation.

PfEMP1 is the major surface antigen of P. falciparum-infected erythrocytes, mediates endothelial adhesion, and displays extreme sequence diversity that underpins antigenic variation. In this issue of Cell Host & Microbe, Tessema et al. (2019) find that antibodies in sera from a pediatric cohort that bind a discrete PfEMP1 subset associate with protection from severe malaria and predict future risk.

In this issue of Cell Host & Microbe, Wu et al. (2019) propose that a bacterial type III effector modifies the host milieu specifically to inhibit competing pathogens with little effect on the inciting pathogen populations. The work raises awareness to examine effectors for niche modification and has implications for the microbial community structure.

Ng et al. (2019) unravel the complex factors that shape commensal gut microbiota susceptibility and resilience to antibiotics. These findings depict the microbiota’s malleable dynamics resulting from compositional changes, environmental variability, and dietary shifts, further informing potential strategies to mitigate incomplete microbiome recovery accompanying antibiotic treatment.

This issue of Cell Host & Microbe highlights the opposite faces of Prevotella copri (P. copri). Tett et al. (2019) and Fehlner-Peach et al. (2019) unravel the complexity of gut dwelling P. copri, whereas Rolhion et al. (2019) explore the P. copri dark side with its ability to potentiate Listeria monocytogenes pathogenicity.

While the normal microbiota has been implicated as a critical defense against invading pathogens, the impact of enteropathogenic infection and host inflammation on intestinal microbial communities has not been elucidated. Using mouse models of Citrobacter rodentium, which closely mimics human diarrheal pathogens inducing host intestinal inflammation, and Campylobacter jejuni infection, as well as chemically and genetically induced models of intestinal inflammation, we demonstrate that host-mediated inflammation in response to an infecting agent, a chemical trigger, or genetic predisposition markedly alters the colonic microbial community. While eliminating a subset of indigenous microbiota, host-mediated inflammation supported the growth of either the resident or introduced aerobic bacteria, particularly of the Enterobacteriaceae family. Further, assault by an enteropathogen and host-mediated inflammation combined to significantly reduce the total numbers of resident colonic bacteria. These findings underscore the importance of intestinal microbial ecosystems in infectious colitis and noninfectious intestinal inflammatory conditions,such as inflammatory bowel disease.

Poxviruses are large DNA viruses that include the causal agent of human smallpox and vaccinia virus. Poxviruses replicate in cytoplasmic foci known as DNA factories. Here we show that a virus-encoded transcription factor, viral mRNA, cellular RNA-binding protein heterodimer G3BP/Caprin-1 (p137), translation initiation factors eIF4E and eIF4G, and ribosomal proteins are concentrated in the same subdomains of cytoplasmic DNA factories. Furthermore, a cell coinfected with two recombinant vaccinia viruses expressing a virus core protein fused to cyan or yellow fluorescent protein displayed separate cyan and yellow factories, indicating that each factory formed from a single genome and was the site of transcription and translation as well as DNA replication. Hijacking of the host translation apparatus within the factory likely enhances the efficiency of virus replication and contributes to the suppression of host protein synthesis, thereby facilitating poxvirus subjugation of the cell.

Antibody binding to the icosahedral arrangement of envelope proteins on the surface of flaviviruses can result in neutralization or enhancement of infection. We evaluated how many antibodies must bind to a given epitope on West Nile virus (WNV) to achieve neutralization. The most potent monoclonal antibodies (mAbs) block infection at concentrations that result in low occupancy of accessible sites on the virion, with neutralization occurring when as few as 30 of 180 envelope proteins are bound. In contrast, weakly neutralizing mAbs recognize fewer sites on the virion and require almost complete occupancy to inhibit WNV infection. For all mAbs studied, enhancement of infection is possible in cells bearing activating Fc-gamma receptors when the number of mAbs docked to the virion is not sufficient for neutralization. Thus, neutralization is best described by a model requiring "multiple hits" with the cumulative functional outcome determined by interplay between antibody affinity and epitope accessibility.

Polyreactive antibodies bind to a variety of structurally unrelated antigens. The function of these antibodies, however, has remained an enigma, and because of their low binding affinity their biological relevance has been questioned. Using a panel of monoclonal polyreactive antibodies, we showed that these antibodies can bind to both Gram-negative and Gram-positive bacteria and acting through the classical complement pathway can inhibit bacterial growth by lysis, generate anaphylatoxin C5a, enhance phagocytosis, and neutralize the functional activity of endotoxin. Polyreactive antibody-enriched, but not polyreactive antibody-reduced, IgM prepared from normal human serum displays antibacterial activity similar to that of monoclonal polyreactive IgM. We conclude that polyreactive antibodies are a major contributor to the broad antibacterial activity of the natural antibody repertoire.

DNA virus infection can elicit the DNA damage response in host cells, including ATM kinase activation and H2AX phosphorylation. This is considered to be the host cell response to replicating viral DNA. In contrast, we show that during infection of macrophages murine gamma-herpesvirus 68 (gammaHV68) actively induces H2AX phosphorylation by expressing a viral kinase (orf36). GammaHV68-encoded orf36 kinase and its EBV homolog, BGLF4, induce H2AX phosphorylation independently of other viral genes. The process requires the kinase domain of Orf36 and is enhanced by ATM. Orf36 is important for gammaHV68 replication in infected animals, and orf36, H2AX, and ATM are all critical for efficient gammaHV68 replication in primary macrophages. Thus, activation of proximal components of the DNA damage signaling response is an active viral kinase-driven strategy required for efficient gamma-herpesvirus replication.