In infectious diseases, extracellular vesicles (EVs) released from a pathogen or pathogen-infected cells can transfer pathogen-derived biomolecules, especially proteins, to target cells and consequently regulate these target cells. For example, malaria is an important tropical infectious disease caused by Plasmodium spp. Previous studies have identified the roles of Plasmodium falciparum-infected red blood cell-derived EVs (Pf-EVs) in the pathogenesis, activation, and modulation of host immune responses. This study investigated the proteomic profiles of Pf-EVs isolated from four P. falciparum strains. We also compared the proteomes of EVs from (i) different EV types (microvesicles and exosomes) and (ii) different parasite growth stages (early- and late-stage). The proteomic analyses revealed that the human proteins carried in the Pf-EVs were specific to the type of Pf-EVs. By contrast, most of the P. falciparum proteins carried in Pf-EVs were common across all types of Pf-EVs. As the proteomics results revealed that Pf-EVs contained invasion-associated proteins, the effect of Pf-EVs on parasite invasion was also investigated. Surprisingly, the attenuation of parasite invasion efficiency was found with the addition of Pf-MVs. Moreover, this effect was markedly increased in culture-adapted isolates compared with laboratory reference strains. Our evidence supports the concept that Pf-EVs play a role in quorum sensing, which leads to parasite growth-density regulation.

CD4⁺ tissue resident memory T cells (T_RMs) are implicated in the formation of persistent HIV reservoirs that are established during the very early stages of infection. The tissue-specific factors that direct T cells to establish tissue residency are not well defined, nor are the factors that establish viral latency. We report that costimulation via MAdCAM-1 and retinoic acid (RA), two constituents of gut tissues, together with TGF-β, promote the differentiation of CD4⁺ T cells into a distinct subset α₄β₇⁺CD69⁺CD103⁺ T_RM-like cells. Among the costimulatory ligands we evaluated, MAdCAM-1 was unique in its capacity to upregulate both CCR5 and CCR9. MAdCAM-1 costimulation rendered cells susceptible to HIV infection. Differentiation of T_RM-like cells was reduced by MAdCAM-1 antagonists developed to treat inflammatory bowel diseases. These finding provide a framework to better understand the contribution of CD4⁺ T_RMs to persistent viral reservoirs and HIV pathogenesis.

Malaria is a life-threatening tropical arthropod-borne disease caused by Plasmodium spp. Monocytes are the primary immune cells to eliminate malaria-infected red blood cells. Thus, the monocyte’s functions are one of the crucial factors in controlling parasite growth. It is reasoned that the activation or modulation of monocyte function by parasite products might dictate the rate of disease progression. Extracellular vesicles (EVs), microvesicles, and exosomes, released from infected red blood cells, mediate intercellular communication and control the recipient cell function. This study aimed to investigate the physical characteristics of EVs derived from culture-adapted P. falciparum isolates (Pf-EVs) from different clinical malaria outcomes and their impact on monocyte polarization. The results showed that all P. falciparum strains released similar amounts of EVs with some variation in size characteristics. The effect of Pf-EV stimulation on M1/M2 monocyte polarization revealed a more pronounced effect on CD14⁺CD16⁺ intermediate monocytes than the CD14⁺CD16⁻ classical monocytes with a marked induction of Pf-EVs from a severe malaria strain. However, no difference in the levels of microRNAs (miR), miR-451a, miR-486, and miR-92a among Pf-EVs derived from virulent and nonvirulent strains was found, suggesting that miR in Pf-EVs might not be a significant factor in driving M2-like monocyte polarization. Future studies on other biomolecules in Pf-EVs derived from the P. falciparum strain with high virulence that induce M2-like polarization are therefore recommended.

Resident memory T cells (T_RMs) help control local immune homeostasis and contribute to tissue protective immune responses. The local cues that guide their differentiation and localization are poorly defined. We demonstrate that MAdCAM-1, a ligand for the gut homing receptor α₄β₇ integrin, in the presence of retinoic acid and TGF-β provide a costimulatory signal that induces blood CD8⁺ T cells to adopt a T_RM -like phenotype. These cells express CD103 (integrin α_E) and CD69, the two major T_RM cell surface markers, along with CD101. They also express CCR5, CCR9 and α₄β₇, three receptors associated with gut homing. A subset also express E-cadherin, a ligand for α_Eβ₇. Fluorescent lifetime imaging indicated an α_Eβ₇ and E-cadherin cis interaction on the plasma membrane. This report advances our understanding of the signals that drive the differentiation of CD8⁺ T cells into T_RMs and provides a means to expand these cells in vitro, thereby affording an avenue to generate more effective tissue specific immunotherapies.

Background: Tissue-resident memory CD4+ T (CD4+ TRM) cells are long-lived, seldom-circulating cells that reside for long periods in most tissues. TRM cells can mount rapid, antigen-specific responses to pathogens and contribute to mucosal barrier homeostasis by regulating commensal interactions. At the intestinal mucosa, the main site of early human immunodeficiency virus (HIV) replication, CD4+ TRM cells may serve as virus targets; however, limited data are available regarding their dynamics during acute HIV-1 infection and antiretroviral treatment. Methods: This was a nested cross-sectional study within a longitudinal cohort. Results: Sigmoid CD4+ TRM (CD69+CD103+) cells had a higher expression of CCR5 than CD4+ non-TRM (CD69−CD103−) cells, suggestive of increased susceptibility to HIV-1 infection. Consistent with this, sigmoid CD4+ TRM but not CD4+ non-TRM cells were depleted/nonreplenished despite long-term ART, regardless of the Fiebig stage at which treatment was initiated during acute HIV infection. In contrast, overall sigmoid CD4+ T cells were comparable in abundance with people living without HIV if treatment was initiated at Fiebig stage I or II, but they were significantly decreased if treatment was initiated at Fiebig stage III or beyond, suggesting preferential early depletion/nonreplenishment of CD4+ TRM cells. The loss/nonreplenishment of sigmoid CD4+ TRM cells was associated with a lower abundance of that short-chain fatty acid–producing commensal bacteria that are crucial for the maintenance of mucosal homeostasis, a higher abundance of opportunistic pathobionts Desulfovibrio, and increased soluble biomarkers of systemic inflammation that drive non-AIDS mortality. Conclusions: Sigmoid CD4+ TRM cells may be early mucosal targets of HIV-1 infection and that their persistent depletion contributes to decreased mucosal barrier function, warranting development of therapeutic strategies that can restore CD4+ TRM cells during HIV treatment.