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The human neonate and infant are unduly susceptible to infection with a wide variety of microbes. This susceptibility is thought to reflect differences from adults in innate and adaptive immunity, but the nature of these differences is incompletely characterized. The innate immune response directs the subsequent adaptive immune response after integrating information from TLRs and other environmental sensors. We set out to provide a comprehensive analysis defining differences in response to TLR ligation between human neonates and adults. In response to most TLR ligands, neonatal innate immune cells, including monocytes and conventional and plasmacytoid dendritic cells produced less IL-12p70 and IFN-α (and consequently induced less IFN-γ), moderately less TNF-α, but as much or even more IL-1β, IL-6, IL-23, and IL-10 than adult cells. At the single-cell level, neonatal innate cells generally were less capable of producing multiple cytokines simultaneously, i.e., were less polyfunctional. Overall, our data suggest a robust if not enhanced capacity of the neonate vs the adult white-blood cell TLR-mediated response to support Th17- and Th2-type immunity, which promotes defense against extracellular pathogens, but a reduced capacity to support Th1-type responses, which promote defense against intracellular pathogens.

HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell-mediated in vivo control of HIV-1. Primary HIV-1-specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or "vertical" immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.

In the present study, we analyzed the functional profile of CD8+ T-cell responses directed against autologous transmitted/founder HIV-1 isolates during acute and early infection, and examined whether multifunctionality is required for selection of virus escape mutations. Seven anti-retroviral therapy-naïve subjects were studied in detail between 1 and 87 weeks following onset of symptoms of acute HIV-1 infection. Synthetic peptides representing the autologous transmitted/founder HIV-1 sequences were used in multiparameter flow cytometry assays to determine the functionality of HIV-1-specific CD8+ T memory cells. In all seven patients, the earliest T cell responses were predominantly oligofunctional, although the relative contribution of multifunctional cell responses increased significantly with time from infection. Interestingly, only the magnitude of the total and not of the poly-functional T-cell responses was significantly associated with the selection of escape mutants. However, the high contribution of MIP-1β-producing CD8+ T-cells to the total response suggests that mechanisms not limited to cytotoxicity could be exerting immune pressure during acute infection. Lastly, we show that epitope entropy, reflecting the capacity of the epitope to tolerate mutational change and defined as the diversity of epitope sequences at the population level, was also correlated with rate of emergence of escape mutants., Author Summary An important role for the polyfunctional T-cell fraction of anti-HIV CD8 responses during chronic HIV infection has previously been suggested. This study characterized the role of polyfunctional T-cells directed against the transmitted/founder virus in the selection of viral escape mutants during acute HIV-1 infection within a unique cohort of individuals recruited within 3 weeks from the onset of symptoms at the time when the virus load was still declining. For the first time, the sequences of the transmitted/founder virus isolated from each patient were used. Interestingly, polyfunctionality was not found to be a pre-requisite for selection of escape mutations. A novel significant correlation is found between the order of appearance of escape mutations in different epitope sequences and both the magnitude of the CD8+ T-cell responses and the degree of entropy of the individual epitopes. A high proportion of the T-cells participating in the total response produced MIP-1β, suggesting that mechanisms not limited to the killing of infected cells might play a relevant role in early infection. This highlights the importance of measuring the quality of the CD8+ lymphocyte response and the sequence of the transmitted virus isolates to better understand the mechanisms of control of HIV replication during acute infection.

The purpose of this investigation was to determine whether the presence of disease-associated bacteria in health-associated plaque correlated with susceptibility to periodontitis over time. Sites of periodontal health were identified in 65 adults. Six months later (recall 1), plaque was collected from sites that remained in periodontal health, and specific bacteria were detected using monoclonal antibodies in a microscopic assay. The spirochete morphogroup was identified by phase contrast microscopy. The relationship between detection at recall 1 and development of periodontitis over two successive 6-month intervals (recalls 2 and 3) was evaluated by means of logistic regression using generalized estimating equations (GEE), from which odds ratios (OR) were estimated and tested for significance. Significant relationships were defined as those having ORs with P < 0.05. Ninety-three of 1,032 sites developed signs of early periodontitis over the 12-month interval between recall 1 and recall 3. The spirochete morphogroup (OR = 3.13, P < 0.001) and pathogen-related oral spirochetes (PROS) (OR = 3.68, P < 0.001) were significantly associated with healthy sites that developed periodontitis. The association of Treponema socranskii was not significant (OR = 3.62, P = 0.0918). Odds ratios for Campylobacter rectus, Eikenella corrodens, and Porphyromonas gingivalis were less than 2.0 and not significant. Treponema denticola was not detected in health-associated plaque from stable health sites and was detected in only three sites that progressed to periodontitis. These findings indicate that the presence of PROS and some unidentified spirochetes in health-associated plaque is associated with increased susceptibility to periodontitis.

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an 'immature' neonatal to a 'mature' adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation.