Effects of intestinal survival surgery on systemic and mucosal immune responses in SIV-infected rhesus macaques

Abstract: Evaluation of cellular immunity in the intestinal lamina propria of rhesus macaques has been used previously to assess protective immunity against mucosal simian immunodeficiency virus (SIV) challenges. As this technique requires survival surgery to obtain jejunal tissue, effects of surgical stress on the immune system were investigated. SIV-specific immune responses, including IgG and IgA binding antibodies in sera and mucosal secretions, IgG and IgA secreting cells in peripheral blood, IgG neutralizing antibodies, T-cell proliferative responses, and interferon-γ secretion by peripheral blood mononuclear cells, were evaluated pre- and post-surgery in macaques immunized with adenovirus-SIV recombinant vaccines and SIV envelope protein and in SIV-infected macaques. No differences in these immune parameters were observed in SIV-naïve, immunized macaques or healthy SIV-infected macaques with regard to surgery. A dramatic increase in total IgA antibody level following surgery in the rectal secretions of one SIV-infected macaque that was rapidly progressing to AIDS and failed to recover from surgery was attributed to an abscess that developed at the intestinal site. To date, nearly 30 other macaques have undergone the intestinal survival surgery, some on more than one occasion, without experiencing any clinical difficulty. Overall, our results suggest that in healthy macaques, intestinal resection survival surgery can be conducted safely. Further, the method can be used to reliably sample the intestinal mucosa without major or persistent impact on humoral or cellular immune responses.     

High‐resolution definition of humoral immune response correlates of effective immunity against HIV

Defining correlates of immunity by comprehensively interrogating the extensive biological diversity in naturally or experimentally protected subjects may provide insights critical for guiding the development of effective vaccines and antibody‐based therapies. We report advances in a humoral immunoprofiling approach and its application to elucidate hallmarks of effective HIV‐1 viral control. Systematic serological analysis for a cohort of HIV‐infected subjects with varying viral control was conducted using both a high‐resolution, high‐throughput biophysical antibody profiling approach, providing unbiased dissection of the humoral response, along with functional antibody assays, characterizing antibody‐directed effector functions such as complement fixation and phagocytosis that are central to protective immunity. Profiles of subjects with varying viral control were computationally analyzed and modeled in order to deconvolute relationships among IgG Fab properties, Fc characteristics, and effector functions and to identify humoral correlates of potent antiviral antibody‐directed effector activity and effective viral suppression. The resulting models reveal multifaceted and coordinated contributions of polyclonal antibodies to diverse antiviral responses, and suggest key biophysical features predictive of viral control.     

Plant‐produced Zika virus envelope protein elicits neutralizing immune responses that correlate with protective immunity against Zika virus in mice

The global Zika virus (ZIKV) outbreak and its link to foetal and newborn microcephaly and severe neurological complications in adults call for the urgent development of ZIKV vaccines. In response, we developed a subunit vaccine based on the ZIKV envelope (E) protein and investigated its immunogenicity in mice. Transient expression of ZIKV E (zE) resulted in its rapid accumulation in leaves of Nicotiana benthamiana plants. Biochemical analysis revealed that plant‐produced ZIKV E (PzE) exhibited specific binding to a panel of monoclonal antibodies that recognize various zE conformational epitopes. Furthermore, PzE can be purified to >90% homogeneity with a one‐step Ni²⁺ affinity chromatography process. PzE are found to be highly immunogenic, as two doses of PzE elicited both potent zE‐specific antibody and cellular immune responses in mice. The delivery of PzE with alum induced a mixed Th1/Th2 immune response, as the antigen‐specific IgG isotypes were a mixture of high levels of IgG1/IgG2c and splenocyte cultures from immunized mice secreted significant levels of IFN‐gamma, IL‐4 and IL‐6. Most importantly, the titres of zE‐specific and neutralizing antibodies exceeded the threshold that correlates with protective immunity against multiple strains of ZIKV. Thus, our results demonstrated the feasibility of plant‐produced ZIKV protein antigen as effective, safe and affordable vaccines against ZIKV.     

A Streptococcus iniae DNA vaccine delivered by a live attenuated Edwardsiella tarda via natural infection induces cross‐genus protection

Edwardsiella tarda and Streptococcus iniae are important fish pathogens. We have reported previously a live E. tarda vaccine based on the attenuated strain TX5RM and a S. iniae DNA vaccine based on the antigen Sia10. In this study, we examined the possibility of constructing a cross‐genus vaccine by taking advantage of the residual infectivity of TX5RM and using it as a carrier host for the natural delivery of a S. iniae DNA vaccine. For this purpose, the recombinant TX5RM, TX5RMS10, was created, which harbours and retains stably the DNA vaccine plasmid pCS10 that expresses Sia10. When flounder were vaccinated with TX5RMS10 via oral and immersion routes, TX5RMS10 was detected in multiple tissues within 12–14 days postvaccination (p.v.). At 7 and 14 days p.v., expression of the DNA vaccine was detected in spleen, kidney and liver. Following E. tarda and S. iniae challenge at one and 2 months p.v., the vaccinated fish exhibited relative per cent survival rates of 69–83%. Immunological analysis indicated that TX5RMS10‐vaccinated fish produced specific serum antibodies and exhibited enhanced expression of a wide range of immune genes.     

Postdispersal nepotism in male long‐tailed macaques (Macaca fascicularis)

Cooperative behaviors are promoted by kin selection if the costs to the actor are smaller than the fitness benefits to the recipient, weighted by the coefficient of relatedness. In primates, cooperation occurs primarily among female dyads. Due to male dispersal before sexual maturity in many primate species, however, it is unknown whether there are sufficient opportunities for selective tolerance and occasional coalitionary support for kin selection to favor male nepotistic support. We studied the effect of the presence of male kin on correlates of male reproductive success (residence time, duration of high dominance rank) in non‐natal male long‐tailed macaques (Macaca fascicularis). We found that “related” (i.e., related at the half‐sibling level or higher) males in a group have a significantly higher probability to remain in the non‐natal group compared to males without relatives. Moreover, males stayed longer in a group when a relative was present at group entry or joined the same group within 3 months upon arrival. Males with co‐residing relatives also maintained a high rank for longer than those without. To our knowledge, this is the first demonstration of a potential nepotistic effect on residence and rank maintenance among non‐natal males in a social system without long‐term alliances.     

Demographic responses to weather fluctuations are context dependent in a long‐lived amphibian

Weather fluctuations have been demonstrated to affect demographic traits in many species. In long‐lived organisms, their impact on adult survival might be buffered by the evolution of traits that reduce variation in interannual adult survival. For example, skipping breeding is an effective behavioral mechanism that may limit yearly variation in adult survival when harsh weather conditions occur; however, this in turn would likely lead to strong variation in recruitment. Yet, only a few studies to date have examined the impact of weather variation on survival, recruitment and breeding probability simultaneously in different populations of the same species. To fill this gap, we studied the impact of spring temperatures and spring rainfall on survival, on reproductive skipping behavior and on recruitment in five populations of a long‐lived amphibian, the yellow‐bellied toad (Bombina variegata). Based on capture–recapture data, our findings demonstrate that survival depends on interactions between age, population and weather variation. Varying weather conditions in the spring result in strong variation in the survival of immature toads, whereas they have little effect on adult toads. Breeding probability depends on both the individual's previous reproductive status and on the weather conditions during the current breeding season, leading to high interannual variation in recruitment. Crucially, we found that the impact of weather variation on demographic traits is largely context dependent and may thus differ sharply between populations. Our results suggest that studies predicting the impact of climate change on population dynamics should be taken with caution when the relationship between climate and demographic traits is established using only one population or few populations. We therefore highly recommend further research that includes surveys replicated in a substantial number of populations to account for context‐dependent variation in demographic processes.     

Multi‐stage disruption of freshwater mussel reproduction by high suspended solids in short‐ and long‐term brooders

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Low concordance of short‐term and long‐term selection responses in experimental Drosophila populations

Experimental evolution is becoming a popular approach to study the genomic selection response of evolving populations. Computer simulation studies suggest that the accuracy of the signature increases with the duration of the experiment. Since some assumptions of the computer simulations may be violated, it is important to scrutinize the influence of the experimental duration with real data. Here, we use a highly replicated Evolve and Resequence study in Drosophila simulans to compare the selection targets inferred at different time points. At each time point, approximately the same number of SNPs deviates from neutral expectations, but only 10% of the selected haplotype blocks identified from the full data set can be detected after 20 generations. Those haplotype blocks that emerge already after 20 generations differ from the others by being strongly selected at the beginning of the experiment and display a more parallel selection response. Consistent with previous computer simulations, our results demonstrate that only Evolve and Resequence experiments with a sufficient number of generations can characterize complex adaptive architectures.     

Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

Disruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved (public) mechanisms of aging (López‐Otín et al., Cell, 153, 2013 and 1194). Human aging is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle aging is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions colocalize with sites of fiber breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia. The nematode Caenorhabditis elegans also exhibits age‐dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans aging. Here, we report identification of 266 novel mtDNA deletions in aging nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (a) mtDNA deletions in nematode are extremely rare, (b) there is no significant age‐dependent increase in mtDNA deletions, and (c) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age‐dependent functional decline commonly observed in C. elegans. Computational modeling of mtDNA dynamics in C. elegans indicates that the lifespan of short‐lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of aging predominantly relevant in long‐lived animals such as humans and rhesus monkey and possibly in rodents.     

cGAS is activated by DNA in a length‐dependent manner

Cytosolic DNA stimulates innate immune responses, including type I interferons (IFN), which have antiviral and immunomodulatory activities. Cyclic GMP‐AMP synthase (cGAS) recognizes cytoplasmic DNA and signals via STING to induce IFN production. Despite the importance of DNA in innate immunity, the nature of the DNA that stimulates IFN production is not well described. Using low DNA concentrations, we show that dsDNA induces IFN in a length‐dependent manner. This is observed over a wide length‐span of DNA, ranging from the minimal stimulatory length to several kilobases, and is fully dependent on cGAS irrespective of DNA length. Importantly, in vitro studies reveal that long DNA activates recombinant human cGAS more efficiently than short DNA, showing that length‐dependent DNA recognition is an intrinsic property of cGAS independent of accessory proteins. Collectively, this work identifies long DNA as the molecular entity stimulating the cGAS pathway upon cytosolic DNA challenge such as viral infections.     

Novel recombinant BCG coexpressing Ag85B,ESAT‐6 and mouse TNF‐α induces significantly enhanced cellular immune and antibody responses in C57BL/6 mice

The recent emergence of multidrug‐resistant and extensively drug‐resistant strains of Mtb and the epidemic of TB in populations co‐infected with human immunodeficiency virus demonstrate that TB remains a leading infectious disease. Moreover, the failure of BCG to protect against this disease indicates that new vaccines against TB are urgently needed. Experimental evidence has revealed that TNF plays a major role in host defense against Mtb in both active and latent phases of infection. Release of TNF, which would induce mycobacteria‐mediated macrophage apoptosis and thus reduce the spread of mycobacteria, is one of the most important and early responses of macrophages challenged with Mtb. In order to identify the usefulness of TNF in improving the effectiveness of TB vaccine, in the current study a novel rBCG strain expressing the fusion gene of Ag85B‐Esat6‐TNF‐α in BCG Danish strain was constructed, and its ability to induce an immune response in C57BL/6 mice evaluated. It was found that immunization with strains of rBCG‐Ag85B‐Esat6‐TNF‐α can induce a stronger immune response than does immunization with rBCG‐Ag85B‐Esat6 or parental BCG. The results indicate that rBCG‐Ag85B‐Esat6‐TNF‐α is a promising candidate for further study.     

A multi‐level response to DNA damage induced by aluminium

Aluminium (Al) ions are one of the primary growth‐limiting factors for plants on acid soils, globally restricting agriculture. Despite its impact, little is known about Al action in planta. Earlier work has indicated that, among other effects, Al induces DNA damage. However, the loss of major DNA damage response regulators, such SOG1, partially suppressed the growth reduction in plants seen on Al‐containing media. This raised the question whether Al actually causes DNA damage and, if so, how. Here, we provide cytological and genetic data corroborating that exposure to Al leads to DNA double‐strand breaks. We find that the Al‐induced damage specifically involves homology‐dependent (HR) recombination repair. Using an Al toxicity assay that delivers higher Al concentrations than used in previous tests, we find that sog1 mutants become highly sensitive to Al. This indicates a multi‐level response to Al‐induced DNA damage in plants.