Immune cell composition varies by age, sex and exposure to social adversity in free-ranging Rhesus Macaques.

Increasing age is associated with dysregulated immune function and increased inflammation-patterns that are also observed in individuals exposed to chronic social adversity. Yet we still know little about how social adversity impacts the immune system and how it might promote age-related diseases. Here, we investigated how immune cell diversity varied with age, sex and social adversity (operationalized as low social status) in free-ranging rhesus macaques. We found age-related signatures of immunosenescence, including lower proportions of CD20 + B cells, CD20 + /CD3 + ratio, and CD4 + /CD8 + T cell ratio - all signs of diminished antibody production. Age was associated with higher proportions of CD3 + /CD8 + Cytotoxic T cells, CD16 + /CD3- Natural Killer cells, CD3 + /CD4 + /CD25 + and CD3 + /CD8 + /CD25 + T cells, and CD14 + /CD16 + /HLA-DR + intermediate monocytes, and lower levels of CD14 + /CD16-/HLA-DR + classical monocytes, indicating greater amounts of inflammation and immune dysregulation. We also found a sex-dependent effect of exposure to social adversity (i.e., low social status). High-status males, relative to females, had higher CD20 + /CD3 + ratios and CD16 + /CD3 Natural Killer cell proportions, and lower proportions of CD8 + Cytotoxic T cells. Further, low-status females had higher proportions of cytotoxic T cells than high-status females, while the opposite was observed in males. High-status males had higher CD20 + /CD3 + ratios than low-status males. Together, our study identifies the strong age and sex-dependent effects of social adversity on immune cell proportions in a human-relevant primate model. Thus, these results provide novel insights into the combined effects of demography and social adversity on immunity and their potential contribution to age-related diseases in humans and other animals.

Infection order outweighs the role of CD4+ T cells in tertiary flavivirus exposure.

The link between CD4+ T and B cells during immune responses to DENV and ZIKV and their roles in cross-protection during heterologous infection is an active area of research. Here we used CD4+ lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during a tertiary flavivirus infection in macaques. We show that CD4+ depletion in DENV/ZIKV-primed animals followed by DENV resulted in dysregulated adaptive immune responses. We show a delay in DENV-specific IgM/IgG antibody titers and binding and neutralization in the DENV/ZIKV-primed CD4-depleted animals but not in ZIKV/DENV-primed CD4-depleted animals. This study confirms the critical role of CD4+ cells in priming an early effective humoral response during sequential flavivirus infections. Our work here suggests that the order of flavivirus exposure affects the outcome of a tertiary infection. Our findings have implications for understanding the complex flavivirus immune responses and for the development of effective flavivirus vaccines.

Recombinant Fasciola hepatica Fatty Acid Binding Protein as a Novel Anti-Inflammatory Biotherapeutic Drug in an Acute Gram-Negative Nonhuman Primate Sepsis Model.

Due to their phylogenetic proximity to humans, nonhuman primates (NHPs) are considered an adequate choice for a basic and preclinical model of sepsis. Gram-negative bacteria are the primary causative of sepsis. During infection, bacteria continuously release the potent toxin lipopolysaccharide (LPS) into the bloodstream, which triggers an uncontrolled systemic inflammatory response leading to death. Our previous research has demonstrated in vitro and in vivo using a mouse model of septic shock that Fh15, a recombinant variant of the Fasciola hepatica fatty acid binding protein, acts as an antagonist of Toll-like receptor 4 (TLR4) suppressing the LPS-induced proinflammatory cytokine storm. The present communication is a proof-of concept study aimed to demonstrate that a low-dose of Fh15 suppresses the cytokine storm and other inflammatory markers during the early phase of sepsis induced in rhesus macaques by intravenous (i.v.) infusion with lethal doses of live Escherichia coli. Fh15 was administered as an isotonic infusion 30 min prior to the bacterial infusion. Among the novel findings reported in this communication, Fh15 (i) significantly prevented bacteremia, suppressed LPS levels in plasma, and the production of C-reactive protein and procalcitonin, which are key signatures of inflammation and bacterial infection, respectively; (ii) reduced the production of proinflammatory cytokines; and (iii) increased innate immune cell populations in blood, which suggests a role in promoting a prolonged steady state in rhesus macaques even in the presence of inflammatory stimuli. This report is the first to demonstrate that a F. hepatica-derived molecule possesses potential as an anti-inflammatory drug against sepsis in an NHP model. IMPORTANCE Sepsis caused by Gram-negative bacteria affects 1.7 million adults annually in the United States and is one of the most important causes of death at intensive care units. Although the effective use of antibiotics has resulted in improved prognosis of sepsis, the pathological and deathly effects have been attributed to the persistent inflammatory cascade. There is a present need to develop anti-inflammatory agents that can suppress or neutralize the inflammatory responses and prevent the lethal consequences of sepsis. We demonstrated here that a small molecule of 14.5 kDa can suppress the bacteremia, endotoxemia, and many other inflammatory markers in an acute Gram-negative sepsis rhesus macaque model. These results reinforce the notion that Fh15 constitutes an excellent candidate for drug development against sepsis.