Melanin-based colorations signal strategies to cope with poor and rich environments

One hypothesis for the maintenance of genetic variation states that alternative genotypes are adapted to different environmental conditions (i.e., genotype-by-environment interaction G×E) that vary in space and time. Although G×E has been demonstrated for morphological traits, little evidence has been given whether these G×E are associated with traits used as signal in mate choice. In three wild bird species, we investigated whether the degree of melanin-based coloration, a heritable trait, covaries with nestling growth rate in rich and poor environments. Variation in the degree of reddish-brown phaeomelanism is pronounced in the barn owl (Tyto alba) and tawny owl (Strix aluco), and variation in black eumelanism in the barn owl and Alpine swift (Apus melba). Melanin-based coloration has been shown to be a criterion in mate choice in the barn owl. We cross-fostered hatchlings to test whether nestlings sired by parents displaying melanin-based colorations to different extent exhibit alternative growth trajectories when raised by foster parents in poor (experimentally enlarged broods) and rich (experimentally reduced broods) environments. With respect to phaeomelanism, barn owl and tawny owl offspring sired by redder parents grew more rapidly in body mass only in experimentally reduced broods. With respect to eumelanism, Alpine swift offspring of darker fathers grew their wings more rapidly only in experimentally enlarged broods, a difference that was not detected in reduced broods. These interactions between parental melanism and offspring growth rate indicate that individuals display substantial plasticity in response to the rearing environment which is associated with the degree of melanism: at least with respect to nestling growth, phaeomelanic and eumelanic individuals are best adapted to rich and poor environments, respectively. It now remains to be investigated why eumelanism and phaeomelanism have a different signaling function and what the lifelong consequences of these melanism-dependent allocation strategies are. This is important to fully appraise the role played by environmental heterogeneity in maintaining variation in the degree of melanin-based coloratio

Cellular and humoral immunity protect against vaginal Zika virus infection in mice

ABSTRACT Zika virus (ZIKV), which can cause devastating disease in fetuses of infected pregnant women, can be transmitted by mosquito inoculation and sexual routes. Little is known about immune protection against sexually transmitted ZIKV. In this study, we show that previous infection through intravaginal or subcutaneous routes with a contemporary Brazilian strain of ZIKV can protect against subsequent intravaginal challenge with a homologous strain. Both routes of inoculation induced high titers of ZIKV-specific and neutralizing antibody in serum and the vaginal lumen. Virus-specific T cells were recruited to and retained in the female reproductive tract after intravaginal and subcutaneous ZIKV infection. Studies in mice with genetic or acquired deficiencies in B and/or T cells demonstrated that both lymphocyte populations redundantly protect against intravaginal challenge in ZIKV-immune animals. Passive transfer of ZIKV-immune IgG or T cells significantly limited intravaginal infection of naive mice, although antibody more effectively prevented dissemination throughout the reproductive tract. Collectively, our experiments begin to establish the immune correlates of protection against intravaginal ZIKV infection, which should inform vaccination strategies in nonpregnant and pregnant women. IMPORTANCE The recent ZIKV epidemic resulted in devastating outcomes in fetuses and may affect reproductive health. Unlike other flaviviruses, ZIKV can be spread by sexual contact as well as a mosquito vector. While previous studies have identified correlates of protection for mosquito-mediated infection, few have focused on immunity against sexual transmission. As exposure to ZIKV via mosquito bite has likely occurred to many living in areas where ZIKV is endemic, our study addresses whether this route of infection can protect against subsequent sexual exposure. We demonstrate that subcutaneous ZIKV infection can protect against subsequent vaginal infection by generating both local antiviral T cell and antibody responses. Our research begins to define the immune correlates of protection for ZIKV infection in the vagina and provides a foundation for testing ZIKV vaccines against sexual transmission. </jats:p

Offspring social network structure predicts fitness in families.

addresses: Centre for Ecology and Conservation, Biosciences, College of Life and Environmental Sciences, University of Exeter, Cornwall Campus, Penryn, Cornwall TR10 9EZ, UK. [email protected]: PMCID: PMC3497231types: Journal Article; Research Support, Non-U.S. Gov'tSocial structures such as families emerge as outcomes of behavioural interactions among individuals, and can evolve over time if families with particular types of social structures tend to leave more individuals in subsequent generations. The social behaviour of interacting individuals is typically analysed as a series of multiple dyadic (pair-wise) interactions, rather than a network of interactions among multiple individuals. However, in species where parents feed dependant young, interactions within families nearly always involve more than two individuals simultaneously. Such social networks of interactions at least partly reflect conflicts of interest over the provision of costly parental investment. Consequently, variation in family network structure reflects variation in how conflicts of interest are resolved among family members. Despite its importance in understanding the evolution of emergent properties of social organization such as family life and cooperation, nothing is currently known about how selection acts on the structure of social networks. Here, we show that the social network structure of broods of begging nestling great tits Parus major predicts fitness in families. Although selection at the level of the individual favours large nestlings, selection at the level of the kin-group primarily favours families that resolve conflicts most effectively

Poor survival outcomes in HER2 positive breast cancer patients with low grade, node negative tumours

We present a retrospective analysis on a cohort of low-grade, node-negative patients showing that human epidermal growth factor receptor 2 (HER2) status significantly affects the survival in this otherwise very good prognostic group. Our results provide support for the use of adjuvant trastuzumab in patients who are typically classified as having very good prognosis, not routinely offered standard chemotherapy, and who as such do not fit current UK prescribing guidelines for trastuzumab

Interferon regulatory factor 5-dependent immune responses in the draining lymph node protect against West Nile Virus infection

Upon activation of Toll-like and RIG-I-like receptor signaling pathways, the transcription factor IRF5 translocates to the nucleus and induces antiviral immune programs. The recent discovery of a homozygous mutation in the immunoregulatory gene guanine exchange factor dedicator of cytokinesis 2 (Dock2(mu/mu)) in several Irf5(−/−) mouse colonies has complicated interpretation of immune functions previously ascribed to IRF5. To define the antiviral functions of IRF5 in vivo, we infected backcrossed Irf5(−/−) × Dock2(wt/wt) mice (here called Irf5(−/−) mice) and independently generated CMV-Cre Irf5(fl/fl) mice with West Nile virus (WNV), a pathogenic neurotropic flavivirus. Compared to congenic wild-type animals, Irf5(−/−) and CMV-Cre Irf5(fl/fl) mice were more vulnerable to WNV infection, and this phenotype was associated with increased infection in peripheral organs, which resulted in higher virus titers in the central nervous system. The loss of IRF5, however, was associated with only small differences in the type I interferon response systemically and in the draining lymph node during WNV infection. Instead, lower levels of several other proinflammatory cytokines and chemokines, as well as fewer and less activated immune cells, were detected in the draining lymph node 2 days after WNV infection. WNV-specific antibody responses in Irf5(−/−) mice also were blunted in the context of live or inactivated virus infection and this was associated with fewer antigen-specific memory B cells and long-lived plasma cells. Our results with Irf5(−/−) mice establish a key role for IRF5 in shaping the early innate immune response in the draining lymph node, which impacts the spread of virus infection, optimal B cell immunity, and disease pathogenesis. IMPORTANCE Although the roles of IRF3 and IRF7 in orchestrating innate and adaptive immunity after viral infection are established, the function of the related transcription factor IRF5 remains less certain. Prior studies in Irf5(−/−) mice reported conflicting results as to the contribution of IRF5 in regulating type I interferon and adaptive immune responses. The lack of clarity may stem from a recently discovered homozygous loss-of-function mutation of the immunoregulatory gene Dock2 in several colonies of Irf5(−/−) mice. Here, using a mouse model with a deficiency in IRF5 and wild-type Dock2 alleles, we investigated how IRF5 modulates West Nile virus (WNV) pathogenesis and host immune responses. Our in vivo studies indicate that IRF5 has a key role in shaping the early proinflammatory cytokine response in the draining lymph node, which impacts immunity and control of WNV infection

A hydrogen peroxide-inactivated virus vaccine elicits humoral and cellular immunity and protects against lethal west nile virus infection in aged mice

West Nile virus (WNV) is an emerging pathogen that is now the leading cause of mosquito-borne and epidemic encephalitis in the United States. In humans, a small percentage of infected individuals develop severe neuroinvasive disease, with the greatest relative risk being in the elderly and immunocompromised, two populations that are difficult to immunize effectively with vaccines. While inactivated and subunit-based veterinary vaccines against WNV exist, currently there is no vaccine or therapy available to prevent or treat human disease. Here, we describe the generation and preclinical efficacy of a hydrogen peroxide (H(2)O(2))-inactivated WNV Kunjin strain (WNV-KUNV) vaccine as a candidate for further development. Both young and aged mice vaccinated with H(2)O(2)-inactivated WNV-KUNV produced robust adaptive B and T cell immune responses and were protected against stringent and lethal intracranial challenge with a heterologous virulent North American WNV strain. Our studies suggest that the H(2)O(2)-inactivated WNV-KUNV vaccine is safe and immunogenic and may be suitable for protection against WNV infection in vulnerable populations

IRF-5-dependent signaling restricts Orthobunyavirus dissemination to the central nervous system

ABSTRACT Interferon (IFN)-regulatory factor 5 (IRF-5) is a transcription factor that induces inflammatory responses after engagement and signaling by pattern recognition receptors. To define the role of IRF-5 during bunyavirus infection, we evaluated Oropouche virus (OROV) and La Crosse virus (LACV) pathogenesis and immune responses in primary cells and in mice with gene deletions in Irf3 , Irf5 , and Irf7 or in Irf5 alone. Deletion of Irf3 , Irf5 , and Irf7 together resulted in uncontrolled viral replication in the liver and spleen, hypercytokinemia, extensive liver injury, and an early-death phenotype. Remarkably, deletion of Irf5 alone resulted in meningoencephalitis and death on a more protracted timeline, 1 to 2 weeks after initial OROV or LACV infection. The clinical signs in OROV-infected Irf5 −/− mice were associated with abundant viral antigen and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in several regions of the brain. Circulating dendritic cell (DC) subsets in Irf5 −/− mice had higher levels of OROV RNA in vivo yet produced lower levels of type I IFN than wild-type (WT) cells. This result was supported by data obtained in vitro , since a deficiency of IRF-5 resulted in enhanced OROV infection and diminished type I IFN production in bone marrow-derived DCs. Collectively, these results indicate a key role for IRF-5 in modulating the host antiviral response in peripheral organs that controls bunyavirus neuroinvasion in mice. IMPORTANCE Oropouche virus (OROV) and La Crosse virus (LACV) are orthobunyaviruses that are transmitted by insects and cause meningitis and encephalitis in subsets of individuals in the Americas. Recently, we demonstrated that components of the type I interferon (IFN) induction pathway, particularly the regulatory transcription factors IRF-3 and IRF-7, have key protective roles during OROV infection. However, the lethality in Irf3 −/− Irf7 −/− (DKO) mice infected with OROV was not as rapid or complete as observed in Ifnar −/− mice, indicating that other transcriptional factors associated with an IFN response contribute to antiviral immunity against OROV. Here, we evaluated bunyavirus replication, tissue tropism, and cytokine production in primary cells and mice lacking IRF-5. We demonstrate an important role for IRF-5 in preventing neuroinvasion and the ensuing encephalitis caused by OROV and LACV

Improved control of SARS-CoV-2 by treatment with nucleocapsid-specific monoclonal antibody

The SARS-CoV-2 spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARSCoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naïve mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific monoclonal antibody (mAb) exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated antibodydependent cellular cytotoxicity (ADCC) against infected cells. These findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based monoclonal antibody therapies to treat COVID-19

Histological Examination in Obtaining a Diagnosis in Patients with Lymphadenopathy in Lima, Peru.

The differential diagnosis for lymphadenopathy is wide and clinical presentations overlap, making obtaining an accurate diagnosis challenging. We sought to characterize the clinical and radiological characteristics, histological findings, and diagnoses for a cohort of patients with lymphadenopathy of unknown etiology. 121 Peruvian adults with lymphadenopathy underwent lymph node biopsy for microbiological and histopathological evaluation. Mean patient age was 41 years (Interquartile Range 26-52), 56% were males, and 39% were HIV positive. Patients reported fever (31%), weight loss (23%), and headache (22%); HIV infection was associated with fever (P < 0.05) and gastrointestinal symptoms (P < 0.05). Abnormalities were reported in 40% of chest X-rays (N = 101). Physicians suspected TB in 92 patients (76%), lymphoma in 19 patients (16%), and other malignancy in seven patients (5.8%). Histological diagnoses (N = 117) included tuberculosis (34%), hyperplasia (27%), lymphoma (13%), and nonlymphoma malignancy (14%). Hyperplasia was more common (P < 0.001) and lymphoma less common (P = 0.005) among HIV-positive than HIV-negative patients. There was a trend toward reduced frequency of caseous necrosis in samples from HIV-positive than HIV-negative TB patients (67 versus 93%, P = 0.055). The spectrum of diagnoses was broad, and clinical and radiological features correlated poorly with diagnosis. On the basis of clinical features, physicians over-diagnosed TB, and under-diagnosed malignancy. Although this may not be inappropriate in resource-limited settings where TB is the most frequent easily treatable cause of lymphadenopathy, diagnostic delays can be detrimental to patients with malignancy. It is important that patients with lymphadenopathy undergo a full diagnostic work-up including sampling for histological evaluation to obtain an accurate diagnosis