To this end, very recently, a formulation of human mAbs (casirivimab and imdevimab) against SARS-CoV-2 was approved for passive immunotherapy in mild and moderately severe COVID-19 cases in India and ...elsewhere. ...it is valuable and timely to summarize the specificity and reactivity of human mAbs against SARS-CoV-2 and its rapidly emerging variants. Primary targets of SARS-CoV-2 therapeutic neutralizing antibodies The spike (S) protein of SARS-CoV-2 is the primary target of neutralizing antibodies (NAbs) (Fig 1A). ...NAbs against SARS-CoV-2 that have either been deployed for therapy or are in advanced stage trials, for the most part, either target the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the spike glycoprotein (Fig 1A and 1B) 1,2. CP, cytoplasmic tail; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2; mAb, monoclonal antibody; NTD, N-terminal domain; PDB, Protein Data Bank; RBD, receptor-binding domain; RBM, receptor-binding motif; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; SP, signal peptide; TM, transmembrane domain. https://doi.org/10.1371/journal.ppat.1009885.g001 Therapeutic COVID-19 mAbs in the clinic and in clinical trials Therapeutic mAbs for COVID-19 treatment have been developed in accelerated time and the pace has been unprecedented for any disease. According to the World Health Organization (WHO), a recognized mutation is elevated to a “variant of concern” (VOC) when the acquisition of a new mutation allows for increased viral transmission, increased fatality, and a significant decrease in the effectiveness of therapy and vaccines.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dengue virus, a mosquito-borne flavivirus, is a causative agent for dengue infection, which manifests with symptoms ranging from mild fever to fatal dengue shock syndrome. The presence of four ...serotypes, against which immune cross-protection is short-lived and serotype cross-reactive antibodies that might enhance infection, pose a challenge to further investigate the role of virus and immune response in pathogenesis. We evaluated the viral and immunological factors that correlate with severe dengue disease in a cohort of pediatric dengue patients in New Delhi. Severe dengue disease was observed in both primary and secondary infections. Viral load had no association with disease severity but high viral load correlated with prolonged thrombocytopenia and delayed recovery. Severe dengue cases had low Th1 cytokines and a concurrent increase in the inflammatory mediators such as IL-6, IL-8 and IL-10. A transient increase in CD14+CD16+ intermediate monocytes was observed early in infection. Sorting of monocytes from dengue patient peripheral blood mononuclear cells revealed that it is the CD14+ cells, but not the CD16+ or the T or B cells, that were infected with dengue virus and were major producers of IL-10. Using the Boruta algorithm, reduced interferon-α levels and enhanced aforementioned pro-inflammatory cytokines were identified as some of the distinctive markers of severe dengue. Furthermore, the reduction in the levels of IL-8 and IL-10 were identified as the most significant markers of recovery from severe disease. Our results provide further insights into the immune response of children to primary and secondary dengue infection and help us to understand the complex interplay between the intrinsic factors in dengue pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During viral infection, effector CD8 T cells contract to form a population of protective memory cells that is maintained by IL-7 and IL-15. The mechanisms that control effector cell death during ...infection are poorly understood. We investigated how short- and long-lived antiviral CD8 T cells differentially used the survival and cell growth pathways PI3K/AKT and JAK/STAT5. In response to IL-15, long-lived memory precursor cells activated AKT significantly better than short-lived effector cells. However, constitutive AKT activation did not enhance memory CD8 T-cell survival but rather repressed IL-7 and IL-15 receptor expression, STAT5 phosphorylation, and BCL2 expression. Conversely, constitutive STAT5 activation profoundly enhanced effector and memory CD8 T-cell survival and augmented homeostatic proliferation, AKT activation, and BCL2 expression. Taken together, these data illustrate that effector and memory cell viability depends on properly balanced PI3K/AKT signaling and the maintenance of STAT5 signaling.
Dengue is emerging as one of the most prevalent mosquito-borne viral diseases of humans. The 11kb RNA genome of the dengue virus encodes three structural proteins (envelope, pre-membrane, capsid) and ...seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), all of which are translated as a single polyprotein that is subsequently cleaved by viral and host cellular proteases at specific sites. Non-structural protein 5 (NS5) is the largest of the non-structural proteins, functioning as both an RNA-dependent RNA polymerase (RdRp) that replicates the viral RNA and an RNA methyltransferase enzyme (MTase) that protects the viral genome by RNA capping, facilitating polyprotein translation. Within the human host, NS5 interacts with several proteins such as those in the JAK-STAT pathway, thereby interfering with anti-viral interferon signalling. This mini-review presents annotated, consolidated lists of known and potential NS5 interactors in the human host as determined by experimental and computational approaches respectively. The most significant protein interactors and the biological pathways they participate in are also highlighted and their implications discussed, along with the specific serotype of dengue virus as appropriate. This information can potentially stimulate and inform further research efforts towards providing an integrative understanding of the mechanisms by which NS5 manipulates the human-virus interface in general and the innate and adaptive immune responses in particular.
As dengue expands globally and many vaccines are under trials, there is a growing recognition of the need for assessing T cell immunity in addition to assessing the functions of neutralizing ...antibodies during these endeavors. While several dengue-specific experimentally validated T cell epitopes are known, less is understood about which of these epitopes are conserved among circulating dengue viruses and also shared by potential vaccine candidates. As India emerges as the epicenter of the dengue disease burden and vaccine trials commence in this region, we have here aligned known dengue specific T cell epitopes, reported from other parts of the world with published polyprotein sequences of 107 dengue virus isolates available from India. Of the 1305 CD4 and 584 CD8 epitopes, we found that 24% and 41%, respectively, were conserved universally, whereas 27% and 13% were absent in any viral isolates. With these data, we catalogued epitopes conserved in circulating dengue viruses from India and matched them with each of the six vaccine candidates under consideration (TV003, TDEN, DPIV, CYD-TDV, DENVax and TVDV). Similar analyses with viruses from Thailand, Brazil and Mexico revealed regional overlaps and variations in these patterns. Thus, our study provides detailed and nuanced insights into regional variation that should be considered for itemization of T cell responses during dengue natural infection and vaccine design, testing and evaluation.
•Co-circulation of all four DENV serotypes seen in 2012–2015 dengue outbreaks in southern India.•Genotype GI of DENV-1 replaced GIII in 2014–15, possibly accounting for DENV-1 predominance.•Novel ...findings include identification of DENV-2 ‘GIVc’ (new lineage), and two clades of DENV-4 GIC.•These genotypic variations may have contributed towards recent dengue outbreaks in southern India.
To genotypically characterize dengue virus (DENV) isolates among dengue-infected children from 2012–13/2014–15 outbreaks in southern India.
Children hospitalized with suspected dengue were tested for dengue RT-PCR targeting Capsid-preMembrane (C-prM) and Envelope (Env) regions. Following virologic confirmation (n=612), a representative selection of DENV isolates (n=99) were sequenced for C-prM, aligned using ClustalW and subjected to phylogenetic analysis by maximum-likelihood method in MEGA6.
In 2012–13 (n=113), DENV-3 (44, 38.9%) and DENV-2 (43, 38.1%) predominated; DENV-1 (22, 19.5%) and DENV-4 (1, 0.9%) were less common. The pattern changed in 2014–15 (n=499), when DENV-1 (329, 65.7%) predominated, followed by DENV-2 (97, 21.2%), DENV-3 (36, 6.7%) and DENV-4 (10, 2.0%). Multiple-serotype co-infections occurred in 2.7% and 5.4% in 2012–13 and 2014–15, respectively. Genotype III (GIII) of DENV-1 predominated (85.7%) in 2012–13, ceding to GI predominance (80.8%) in 2014–15. Among DENV-2, 71.9% (23/32) showed distinct clustering suggesting a new lineage, ‘GIVc’. All tested DENV-4 were GIC, whose clustering pattern showed the emergence of two distinct clades.
New genotypic/lineage variations in DENV-1 and DENV-2 may have influenced the magnitude and severity of dengue epidemics in southern India during this period. These findings emphasize the role of active surveillance of DENV serotypes/genotypes in aiding outbreak control and vaccine studies.
Over the past two decades, many countries have reported a steady decline in reported cases of malaria, and a few countries, like China, have been declared malaria-free by the World Health ...Organization. In 2020 the number of deaths from malaria has declined since 2000. The COVID-19 pandemic has adversely affected overall public health efforts and thus it is feasible that there might be a resurgence of malaria. COVID-19 and malaria share some similarities in the immune responses of the patient and these two diseases also share overlapping early symptoms such as fever, headache, nausea, and muscle pain/fatigue. In the absence of early diagnostics, there can be a misdiagnosis of the infection(s) that can pose additional challenges due to delayed treatment. In both SARS-CoV-2 and Plasmodium infections, there is a rapid release of cytokines/chemokines that play a key role in disease pathophysiology. In this review, we have discussed the cytokine/chemokine storm observed during COVID-19 and malaria. We observed that: (1) the severity in malaria and COVID-19 is likely a consequence primarily of an uncontrolled ‘cytokine storm’; (2) five pro-inflammatory cytokines (IL-6, IL-10, TNF-α, type I IFN, and IFN-γ) are significantly increased in severe/critically ill patients in both diseases; (3) Plasmodium and SARS-CoV-2 share some similar clinical manifestations and thus may result in fatal consequences if misdiagnosed during onset.
SARS-CoV-2; COVID-19; Plasmodium; Malaria; Cytokine storm; Immune impairment.
Chikungunya virus (CHIKV), an arthropod‐borne Alphavirus is responsible for chikungunya disease. Arthralgia and arthritis are the major symptom. Some patients recover early while others for a very ...long time. This study provides, epidemiology and molecular characterization of three whole‐genome sequences of CHIKV and assessed phylogenetic analysis, physiological properties, antigenicity, and B‐cell epitope prediction by in silico. We report the clinical epidemiology of 325 suspected patients. Of these, 118 (36.30%) were confirmed CHIKV positive by either PCR or ELISA. Clinical analysis showed joint pain, joint swelling and headache were frequent and significant features. Phylogenie analysis showed the currently circulating strain is in close clustring to Africa, Uganda, and Singapore CHIKV strains. Molecular characterization by WGS was done. Thirty eight amino acid changes in the nonstructural proteins were found with respect to the S27 (ECSA) strain. Of these five located in nsP2. Similarly, 34 amino acid changes in structural proteins were observed. The major change was notice; in E3 protein hydropathicity −0.281 to −0.362, in E2 isoelectric point (pI) 8.24 to 8.37, instability index 66.08 to 71.062, aliphatic index varied from 74.69 to 68.59 and E3 75.79 to 70.05. In nsP1 protein pI varies from 6.62 to 8.04, while no other change was observed in structural and nonstructural protein. The linear B‐cell epitopes, position, and number varied with the mutation. The molecular characterizations of WGS demonstrate the observation of protein, antigenicity with respect to the mutation.
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