Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV.

Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1ß, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (TregDys)/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the TregDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal TregDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction.

Oral immune dysfunction is associated with the expansion of FOXP3+PD-1+Amphiregulin+ T cells during HIV infection.

Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV, despite treatment with combined anti-retroviral therapy, but the underlying immune mechanisms are poorly understood. Here we report that the altered immune landscape of the oral mucosa of HIV-positive patients on therapy involves increased TLR and inflammasome signaling, localized CD4+ T cell hyperactivation, and, counterintuitively, enrichment of FOXP3+ T cells. HIV infection of oral tonsil cultures in vitro causes an increase in FOXP3+ T cells expressing PD-1, IFN-γ, Amphiregulin and IL-10. These cells persist even in the presence of anti-retroviral drugs, and further expand when stimulated by TLR2 ligands and IL-1ß. Mechanistically, IL-1ß upregulates PD-1 expression via AKT signaling, and PD-1 stabilizes FOXP3 and Amphiregulin through a mechanism involving asparaginyl endopeptidase, resulting in FOXP3+ cells that are incapable of suppressing CD4+ T cells in vitro. The FOXP3+ T cells that are abundant in HIV-positive patients are phenotypically similar to the in vitro cultured, HIV-responsive FOXP3+ T cells, and their presence strongly correlates with CD4+ T cell hyper-activation. This suggests that FOXP3+ T cell dysregulation might play a role in the mucosal immune dysfunction of HIV patients on therapy.

Treating colon cancers with a non-conventional yet strategic approach: An overview of various nanoparticulate systems.

Regardless of progress in therapy management which are developed for colon cancer (CC), it remains the third most common cause of mortality due to cancers around the world. Conventional medicines pose side effects due to untoward action on non-target cells. Their inability to deliver drugs to the affected regions of the colon locally, in a reproducible manner raises a concern towards the efficacy of therapy. In this regard, nanoparticles emerged as a promising drug delivery system due to their flexibility in designing, drug release modulation and cancer cell targeting. Not only are nanoparticles making their way into colon cancer research in the revolution of conventional onco-therapeutics, but they also offer promising scope in the development of colon cancer vaccines and theranostic tools. However, there are challenges with respect to drug delivery using nanoparticles, which may hamper the delivery of these novel carriers to the colon. The present review addresses recent advents in nanotechnology for colon-specific drug delivery (CDDS) which may help to overcome the existing challenges and intends to recognize futuristic potentials in the treatment of CC with CDDS.

Transforming growth factor-ß1 sustains the survival of Foxp3(+) regulatory cells during late phase of oropharyngeal candidiasis infection.

As CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play crucial immunomodulatory roles during infections, one key question is how these cells are controlled during antimicrobial immune responses. Mechanisms controlling their homeostasis are central to ensure efficient protection against pathogens, as well as to control infection-associated immunopathology. Here we studied how their viability is regulated in the context of mouse oropharyngeal candidiasis (OPC) infection, and found that these cells show increased protection from apoptosis during late phase of infection and reinfection. Tregs underwent reduced cell death because they are refractory to T cell receptor restimulation-induced cell death (RICD). We confirmed their resistance to RICD, using mouse and human Tregs in vitro, and by inducing α-CD3 antibody-mediated apoptosis in vivo. The enhanced viability is dependent on increased transforming growth factor-ß1 (TGF-ß1) signaling that results in upregulation of cFLIP (cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein) in Tregs. Protection from cell death is abrogated in the absence of TGF-ß1 signaling in Tregs during OPC infection. Taken together, our data unravel the previously unrecognized role of TGF-ß1 in promoting Treg viability, coinciding with the pronounced immunomodulatory role of these cells during later phase of OPC infection, and possibly other mucosal infections.

Effect of midazolam pretreatment on induction dose requirements of propofol in combination with fentanyl in younger and older adults.

In a double-blind, randomised trial, we compared the effects of pretreatment with midazolam at two different doses (0.025 and 0.05 mg x kg(-1)), with placebo, on the induction dose requirements of propofol in two different age groups. We enrolled 120 patients: 60 younger patients (aged 18-35 years) and 60 older patients (aged over 60 years). All patients received 0.75 microg x kg(-1) of fentanyl, plus a blinded pretreatment with either saline or one of two doses of midazolam. Induction continued with a fixed rate infusion of propofol. Propofol dose requirement was recorded, as were cardiovascular parameters and the occurrence of significant apnoea (> 60 s). Midazolam pretreatment was associated with a significant reduction in propofol dose requirement in both younger and older patients. The reduction in older patients was significantly greater than the equivalent response in younger groups. There was no demonstrable benefit in terms of improved cardiovascular stability or reduction in the incidence of apnoea. Caution is advised in the use of midazolam as an agent for co-induction with propofol in the elderly.