MAVS Is essential for primary CD4 + T cell immunity but not for recall T cell responses following an attenuated West Nile virus infection

ABSTRACT The use of pathogen recognition receptor (PRR) agonists and the molecular mechanisms involved have been the major focus of research in individual vaccine development. West Nile virus (WNV) nonstructural (NS) 4B-P38G mutant has several features for an ideal vaccine candidate, including significantly reduced neuroinvasiveness, induction of strong adaptive immunity, and protection of mice from wild-type (WT) WNV infection. Here, we determined the role of mitochondrial antiviral signaling protein (MAVS), the adaptor protein for RIG-I-like receptor in regulating host immunity against the NS4B-P38G vaccine. We found that Mavs −/− mice were more susceptible to NS4B-P38G priming than WT mice. Mavs −/− mice had a transiently reduced production of antiviral cytokines and an impaired CD4 + T cell response in peripheral organs. However, antibody and CD8 + T cell responses were minimally affected. NS4B-P38G induced lower type I interferon (IFN), IFN-stimulating gene, and proinflammatory cytokine responses in Mavs −/− dendritic cells and subsequently compromised the antigen-presenting capacity for CD4 + T cells. Interestingly, Mavs −/− mice surviving NS4B-P38G priming were all protected from a lethal WT WNV challenge. NS4B-P38G-primed Mavs −/− mice exhibited equivalent levels of protective CD4 + T cell recall response, a modestly reduced WNV-specific IgM production, but more robust CD8 + T cell recall response. Taken together, our results suggest that MAVS is essential for boosting optimal primary CD4 + T cell responses upon NS4B-P38G vaccination and yet is dispensable for host protection and recall T cell responses during secondary WT WNV infection. IMPORTANCE The production of innate cytokines induced by the recognition of pathogen recognition receptors (PRRs) via their cognate ligands are critical for enhancing antigen-presenting cell functions and influencing T cell responses during microbial infection. The use of PRR agonists and the underlying molecular mechanisms have been the major focus in individual vaccine development. Here, we determined the role of mitochondrial antiviral-signaling protein (MAVS), the adaptor protein for RIG-I like receptor in regulating host immunity against the live attenuated West Nile virus (WNV) vaccine strain, the nonstructural (NS) 4B-P38G mutant. We found that MAVS is important for boosting optimal primary CD4 + T cell response during NS4B-P38G vaccination. However, MAVS is dispensable for memory T cell development and host protection during secondary wild-type WNV infection. Overall, these results may be utilized as a paradigm to aid in the rational development of other efficacious live attenuated flavivirus vaccines

Host immunity in the protective response to vaccination with heat-killed Burkholderia mallei

<p>Abstract</p> <p>Background</p> <p>We performed initial cell, cytokine and complement depletion studies to investigate the possible role of these effectors in response to vaccination with heat-killed <it>Burkholderia mallei </it>in a susceptible BALB/c mouse model of infection.</p> <p>Results</p> <p>While protection with heat-killed bacilli did not result in sterilizing immunity, limited protection was afforded against an otherwise lethal infection and provided insight into potential host protective mechanisms. Our results demonstrated that mice depleted of either B cells, TNF-α or IFN-γ exhibited decreased survival rates, indicating a role for these effectors in obtaining partial protection from a lethal challenge by the intraperitoneal route. Additionally, complement depletion had no effect on immunoglobulin production when compared to non-complement depleted controls infected intranasally.</p> <p>Conclusion</p> <p>The data provide a basis for future studies of protection via vaccination using either subunit or whole-organism vaccine preparations from lethal infection in the experimental BALB/c mouse model. The results of this study demonstrate participation of B220⁺cells and pro-inflammatory cytokines IFN-γ and TNF-α in protection following HK vaccination.</p

TC83 Sequelae

Long-term neurological complications, termed sequelae, can result from viral encephalitis, which are not well understood. In human survivors, alphavirus encephalitis can cause severe neurobehavioral changes, in the most extreme cases, a schizophrenic-like syndrome. In the present study, we aimed to adapt an animal model of alphavirus infection survival to study the development of these long-term neurological complications. Upon low-dose infection of wild-type C57B/6 mice, asymptomatic and symptomatic groups were established and compared to mock-infected mice to measure general health and baseline neurological function, including the acoustic startle response and prepulse inhibition paradigm. Prepulse inhibition is a robust operational measure of sensorimotor gating, a fundamental form of information processing. Deficits in prepulse inhibition manifest as the inability to filter out extraneous sensory stimuli. Sensory gating is disrupted in schizophrenia and other mental disorders, as well as neurodegenerative diseases. Symptomatic mice developed deficits in prepulse inhibition that lasted through 6 months post infection; these deficits were absent in asymptomatic or mock-infected groups. Accompanying prepulse inhibition deficits, symptomatic animals exhibited thalamus damage as visualized with H&E staining, as well as increased GFAP expression in the posterior complex of the thalamus and dentate gyrus of the hippocampus. These histological changes and increased GFAP expression were absent in the asymptomatic and mock-infected animals, indicating that glial scarring could have contributed to the prepulse inhibition phenotype observed in the symptomatic animals. This model provides a tool to test mechanisms of and treatments for the neurological sequelae of viral encephalitis and begins to delineate potential explanations for the development of such sequelae post infection

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ABSTRACT. Objective. Macrophage activation syndrome (MAS) is a well described, but purportedly uncommon manifestation of systemic juvenile idiopathic arthritis (SJIA). There is evidence to suggest that macrophage activation is integral to the pathogenesis of SJIA. Accordingly, many patients with SJIA may have evidence of mild MAS that is not appreciated clinically. We investigated the prevalence of occult MAS in children with SJIA by reviewing bone marrow aspirates (BMA). Methods. Patients diagnosed with SJIA who underwent bone marrow aspiration were identified retrospectively. Patients admitted with a diagnosis of fever of unknown origin and discharged with a diagnosis other than SJIA or malignancy, and who had a BMA, were identified as controls. The BMA were reviewed by a single hematopathologist for evidence of MAS, ranging from activated macrophages to frank hemophagocytic cells. Results. Eight of 15 (53%) patients with SJIA had BMA suggestive of MAS. Two of 15 patients (13%) were diagnosed clinically with MAS. Three patients (20%) were noted to have frank hemophagocytosis, only one of whom was diagnosed with MAS clinically. There were no statistically significant differences in the laboratory values for the patients with and without evidence of MAS on BMA. There was no evidence of increased macrophage activity or hemophagocytosis in any of the control BMA. Conclusion. Occult MAS appears to be common in patients with SJIA who undergo BMA. This suggests that macrophage activation may be integral to the pathogenesis of SJIA, with implications for treatment. (First Releas

Predicted enhanced human propensity of current avian-like H1N1 swine influenza virus from China

Influenza A virus (IAV) subtypes against which little or no pre-existing immunity exists in humans represent a serious threat to global public health. Monitoring of IAV in animal hosts is essential for early and rapid detection of potential pandemic IAV strains to prevent their spread. Recently, the increased pandemic potential of the avian-like swine H1N1 IAV A/swine/Guangdong/104/2013 has been suggested. The virus is infectious in humans and the general population seems to lack neutralizing antibodies against this virus. Here we present an in silico analysis that shows a strong human propensity of this swine virus further confirming its pandemic potential. We suggest mutations which would further enhance its human propensity. We also propose conserved antigenic determinants which could serve as a component of a prepandemic vaccine. The bioinformatics tool, which can be used to further monitor the evolution of swine influenza viruses towards a pandemic virus, are described here and are made publically available (http://www.vin.bg.ac.rs/180/tools/iav-mon.php; http://www.biomedprotection.com/iav-mon.php)

Common variable immunodeficiency syndrome with right aortic arch: a case report

BACKGROUND: Common variable immunodificiency syndrome predominantly affects adults. It is characterized by low production of all the major classes of immunoglobulins. We report a case of common variable immunodeficiency syndrome with right aortic arch. An association of right-sided arch and common variable immunodificiency syndrome has not been previously reported. CASE PRESENTATION: A 41-year-old female patient presented with a history of recurrent pneumonia, sinusitis, otitis media, diarrhoea, cystitis since childhood. Biochemical and immunocytochemical analysis revealed common variable immunodeficiency syndrome and radiological evaluation confirmed right aortic arch and aberrant left subclavian artery. CONCLUSION: Common variable immunodeficiency syndrome syndrome is a clinical entity that should be kept in mind in patients with recurrent infections of different sites

Editorial: Coronavirus disease (COVID-19): pathophysiology, epidemiology, clinical management and public health response

During a pandemic, there are multiple concurrent clinical and scientific priorities, including the need to understand the pathophysiology of the disease, the different modes of transmission, how patient care can be optimized, as well as the need to develop mathematical models that can now cast and forecast the progression of infections within given populations and/or geographical regions. When the current SARS-CoV2 pandemic was declared a Public Health Emergency of International Concern by the World Health Organization, a formal declaration of its gravity, it became evident that there was an acute need to understand all of the above aspects. In doing so, by 11th February 2020, a special topic, entitled “Coronavirus Disease (COVID-19): Pathophysiology, Epidemiology, Clinical Management and Public Health Response,” was initiated with a dedicated team of handling editors to facilitate the timely peer-review and publication of relevant manuscripts (1). Frontiers, as the publisher of this special topic, took the bold step of waiving any article processing charges so that financial constraints would not be a barrier to communicating crucial information about the pandemic to a broad audience. Furthermore, this was the most extensive special topic to date in the Frontiers portfolio, in terms of the numbers of participating Frontiers journals, disciplines, and sections. This reflected the acute need for the scientific community to understand the many aspects of the pandemic. This special Research Topic captured the entire first wave in the northern hemisphere, from February to May 2020, and the intensity of the associated editorial work is evident by the reported numbers. Within 4 months, 194 abstracts were received; in total 851 manuscripts were submitted, of which 453 were rejected while 398 were published. From the scientific community perspective, by June 2020 the special topic achieved over 2 million views, by December 2020 over 4 million views, and by August 2021 over 8 million views. As an example of the breadth of subjects covered, manuscripts included the attempt by Larsen et al. to model the onset of symptoms of COVID-19; the observed gender differences on COVID-19 patients’ severity and mortality by Jin et al., the correlation between poverty levels and rates of COVID-19 incidence and death in the United States by Finch and Finch, as well as the careful review of the cytokine storm in COVID-19 (Tang et al.

Ibuprofen, a traditional drug that may impact the course of COVID-19 new effective formulation in nebulizable solution

The traditional formulation of ibuprofen is poorly soluble in water, so the administered dose must be 10 times higher than the dose required for a therapeutic effect. The development of a hydrosoluble form of ibuprofen can be a strategy to reach a high concentration in the lungs by using modern inhalation devices. Therefore, the development of an inhalable formulation with high bioavailability in the lungs was the leitmotiv of our investigation. The hypertonic ibuprofen solution to be nebulized (NIH) presents great relevant characteristics: bactericidal, virucidal, mucolytic and has a known anti-inflammatory property. Bactericidal and virucidal effects are related to the physico-chemical properties of Na-ibuprofenate as an amphipathic molecule. It has the capability to insert into the bilayer membranes destabilizing the structure, altering its biological properties and avoiding the duplication or infection. Our preliminary results indicate that the presence of this high ionic strength solution reduces 10 times the amount of ibuprofen necessary to kill bacteria, but also the time to kill 1x106 bacteria, from 4 h (in its absence) to only three minutes (in its presence). That was observed using Pseudomona aeruginosa, methicillin-resistant Staphylococcus aureus and Burkholderia cepacia. Also, ?in vitro´´ ibuprofen demonstrated virucidal activity against the so-called enveloped virus, a family that includes coronavirus strain (2019-nCoV). We observed too, the markedly reduced local inflammation in the airways after administering NIH lays on its ability to inhibit the enzyme cyclooxygenase and to markedly diminish reactive oxygen species (ROS). Other investigators also showed the importance of actin in the rapid spread of virus infection. Furthermore, reorganization of the actin filaments is a key step in lung inflammation induced by systemic inflammatory responses caused by SARS-CoV-2. These findings suggest that the interaction between actin proteins and S1 is involved in the 2019-nCoV infection and pathogenesis.Consequently, the possibility of interfering in this interaction could represent a valid hypothesis for the development of promising therapeutic and prevention strategies. In conclusion, we consider that treating people with COVID-19 with NIH may be beneficial and an opportunity to contribute for the current global health emergency.publishedVersionFil: García Canclini, Néstor. Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. Instituto de Investigaciones en Ciencias de la Salud; Argentina.Fil: García Canclini, Néstor. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas; Argentina.Fil: Porta, Daniela Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. Instituto de Investigaciones en Ciencias de la Salud; Argentina.Fil: Porta, Daniela Josefina. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas; Argentina.Fil: Muñoz, Sonia Edith. Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. Instituto de Investigaciones en Ciencias de la Salud; Argentina; Argentina.Fil: Muñoz, Sonia Edith. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas; Argentina.Fil: Alasino, Roxana Valeria. Ministerio de Ciencia y Tecnología de Córdoba. Centro de Excelencia en Productos y Procesos de Córdoba; Argentina.Fil: Beltramo, Dante MiguelIcon. Ministerio de Ciencia y Tecnología de Córdoba. Centro de Excelencia en Productos y Procesos de Córdoba; Argentina

One Health epidemic preparedness: Biosafety quality improvement training in Nigeria

Background and Aim: One of the key components of the O ne Health approach to epidemic preparedness is raising awareness and increasing the knowledge of emerging infectious diseases, prevention, and risk reduction. However, related research can involve significant risks to biosafety and biosecurity. For this purpose, we organized a multidisciplinary biosafety hands-on workshop to inform and increase the knowledge of infectious diseases and risk mitigation. This study aimed to describe the process and outcome of a hands-on biosafety training program using a One Health a pproach across a multidisciplinary and multi-specialty group in Nigeria. Materials and Methods: A face-to-face hands-on training for 48 participants was organized by the West African Center for Emerging Infectious Diseases (WAC-EID) at the Jos University Teaching Hospital, serving as a lead institution for the Nigeria project site. Topics covered included (1) an overview of the WAC-EID research; (2) overview of infection prevention and control; (3) safety in animal handling and restraint, sample collection, and processing; (4) safety in field studies including rodent, bird and bat handling; (5) safety practices in the collection of mosquito and other arthropod vectors; (6) personal protective equipment training (disinfection, donning and doffing); and (7) safety in sample collection, labeling, and transportation. The program was executed using a mixed method of slide presentations, practical hands-on sessions, and video demonstrations. Pre- and post-course evaluation assessments and evaluation measures were used to assess training. Results: A total of 48 trainees participated in this training, with 12 (25%), 16 (33.3%), 14 (29.2%), 6 (12.5%) categorized as ornithology, entomology, mammalogy, and clinical interest groups, respectively. The pass rate for the pre-test was 29.4%, while for the post-test, it was 57.1%, or a 28% improvement. 88.6% of the trainees rated the training as relevant to them. Conclusion: Didactic and hands-on biosafety training is relevant in this era of zoonotic epidemics and pandemic preparedness. During this training program, there was a clear demonstration of knowledge transfer that can change the current practices of participants and improve the safety of infectious diseases research

Vaccine-elicited receptor-binding site antibodies neutralize two New World hemorrhagic fever arenaviruses

While five arenaviruses cause human hemorrhagic fevers in the Western Hemisphere, only Junin virus (JUNV) has a vaccine. The GP1 subunit of their envelope glycoprotein binds transferrin receptor 1 (TfR1) using a surface that substantially varies in sequence among the viruses. As such, receptor-mimicking antibodies described to date are type-specific and lack the usual breadth associated with this mode of neutralization. Here we isolate, from the blood of a recipient of the live attenuated JUNV vaccine, two antibodies that cross-neutralize Machupo virus with varying efficiency. Structures of GP1–Fab complexes explain the basis for efficient cross-neutralization, which involves avoiding receptor mimicry and targeting a conserved epitope within the receptor-binding site (RBS). The viral RBS, despite its extensive sequence diversity, is therefore a target for cross-reactive antibodies with activity against New World arenaviruses of public health concern