Macrophages in the gastrointestinal mucosa represent the largest pool of tissue macrophages in the body. In order to maintain mucosal homeostasis, resident intestinal macrophages uniquely do not express the lipopolysaccharide (LPS) co-receptor CD14 or the IgA (CD89) and IgG (CD16, 32, and 64) receptors, yet prominently display Toll-like receptors (TLRs) 3-9. Remarkably, intestinal macrophages also do not produce proinflammatory cytokines in response to TLR ligands, likely because of extracellular matrix (stroma) transforming growth factor-β dysregulations of nuclear factor (NF)-κB signal proteins and, via Smad signaling, expression of IκBα, thereby inhibiting NF-κB-mediated activities. Thus, in noninflamed mucosa, resident macrophages are inflammation anergic but retain avid scavenger and host defense function, an ideal profile for macrophages in close proximity to gut microbiota. In the event of impaired epithelial integrity during intestinal infection or inflammation, however, blood monoctyes also accumulate in the lamina propria and actively pursue invading microorganisms through uptake and degradation of the organism and release of inflammatory mediators. Consequently, resident intestinal macrophages are inflammation adverse, but when the need arises, they receive assistance from newly recruited circulating monocytes.

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Human intestinal macrophages contribute to tissue homeostasis in noninflamed mucosa through profound down-regulation of pro-inflammatory cytokine release. Here, we show that this down-regulation extends to Toll-like receptor (TLR)-induced cytokine release, as intestinal macrophages expressed TLR3–TLR9 but did not release cytokines in response to TLR-specific ligands. Likely contributing to this unique functional profile, intestinal macrophages expressed markedly down-regulated adapter proteins MyD88 and Toll interleukin receptor 1 domain-containing adapter-inducing interferon β, which together mediate all TLR MyD88-dependent and -independent NF-κB signaling, did not phosphorylate NF-κB p65 or Smad-induced IκBα, and did not translocate NF-κB into the nucleus. Importantly, transforming growth factor-β released from intestinal extracellular matrix (stroma) induced identical down-regulation in the NF-κB signaling and function of blood monocytes, the exclusive source of intestinal macrophages. Our findings implicate stromal transforming growth factor-β-induced dysregulation of NF-κB proteins and Smad signaling in the differentiation of pro-inflammatory blood monocytes into noninflammatory intestinal macrophages.

RNAs of many viruses are translated efficiently in the absence of a 5 cap structure. The tobacco necrosis virus (TNV) genome is an uncapped, nonpolyadenylated RNA whose translation mechanism has not been well investigated. Computational analysis predicted a cap-independent translation element (TE) within the 3 untranslated region (3 UTR) of TNV RNA that resembles the TE of barley yellow dwarf virus (BYDV), a luteovirus. Here we report that such a TE does indeed exist in the 3 UTR of TNV strain D. Like the BYDV TE, the TNV TE (i) functions both in vitro and in vivo, (ii) requires additional sequence for cap-independent translation in vivo, (iii) has a similar secondary structure and the conserved sequence CGGAUCCUGGGAA ACAGG, (iv) is inactivated by a four-base duplication in this conserved sequence, (v) can function in the 5 UTR, and (vi) when located in its natural 3 location, may form long-distance base pairing with the viral 5 UTR that is conserved and probably required. The TNV TE differs from the BYDV TE by having only three helical domains instead of four. Similar structures were found in all members of the Necrovirus genus of the Tombusviridae family, except satellite tobacco necrosis virus, which harbors a different 3 cap-independent translation domain. The presence of the BYDV-like TE in select genera of different families indicates that phylogenetic distribution of TEs does not follow standard viral taxonomic relationships. We propose a new class of cap-independent TE called BYDV-like TE.

Citation Shen R, Richter HE, Smith PD. Early HIV‐1 target cells in human vaginal and ectocervical mucosa. Am J Reprod Immunol 2011; 65: 261–267 After translocation through the pleuristratified epithelium of the lower female genital tract, HIV‐1 encounters potential target mononuclear cells in the lamina propria of the vagina and ectocervix. Here we show that each major type of genital mononuclear cells, including dendritic cells (DCs), macrophages and lymphocytes, are susceptible to HIV‐1 in vitro. Among suspensions of vaginal and ectocervical mononuclear cells, DCs were the first cells to take up virus, containing GFP‐tagged virions as early as 15 min after exposure. At 2 hr after exposure, DCs still contained the largest proportion of HIV‐1+ cells compared to lamina propria macrophages and lymphocytes from the same mucosal compartment. By 4 days, however, lymphocytes from both vaginal and ectocervical mucosa supported the highest level of HIV‐1 replication. Genital macrophages from the same mucosal tissues also were permissive to HIV‐1, in sharp contrast to intestinal macrophages, which we have shown previously do not support HIV‐1 replication. Thus, among human vaginal and ectocervical mononuclear target cells, DCs are the first to take up HIV‐1 and T cells support the most robust viral replication. Further characterization of the parameters of HIV‐1 infection in genital mononuclear cells will enhance our understanding of HIV‐1 infection in the female genital tract.