Efficient Transmission In Humans Research Articles

Characterization of an Emergent Chicken H3N8 Influenza Virus in Southern China: a Potential Threat to Public Health.

Although influenza A viruses of several subtypes have occasionally infected humans, to date only those of the H1, H2, and H3 subtypes have led to pandemics and become established in humans. The detection of two human infections by avian H3N8 viruses in April and May of 2022 raised pandemic concerns. Recent studies have shown the H3N8 viruses were introduced into humans from poultry, although their genesis, prevalence, and transmissibility in mammals have not been fully elucidated. Findings generated from our systematic influenza surveillance showed that this H3N8 influenza virus was first detected in chickens in July 2021 and then disseminated and became established in chickens over wider regions of China. Phylogenetic analyses revealed that the H3 HA and N8 NA were derived from avian viruses prevalent in domestic ducks in the Guangxi-Guangdong region, while all internal genes were from enzootic poultry H9N2 viruses. The novel H3N8 viruses form independent lineages in the glycoprotein gene trees, but their internal genes are mixed with those of H9N2 viruses, indicating continuous gene exchange among these viruses. Experimental infection of ferrets with three chicken H3N8 viruses showed transmission through direct contact and inefficient transmission by airborne exposure. Examination of contemporary human sera detected only very limited antibody cross-reaction to these viruses. The continuing evolution of these viruses in poultry could pose an ongoing pandemic threat. IMPORTANCE A novel H3N8 virus with demonstrated zoonotic potential has emerged and disseminated in chickens in China. It was generated by reassortment between avian H3 and N8 virus(es) and long-term enzootic H9N2 viruses present in southern China. This H3N8 virus has maintained independent H3 and N8 gene lineages but continues to exchange internal genes with other H9N2 viruses to form novel variants. Our experimental studies showed that these H3N8 viruses were transmissible in ferrets, and serological data suggest that the human population lacks effective immunological protection against it. With its wide geographical distribution and continuing evolution in chickens, other spillovers to humans can be expected and might lead to more efficient transmission in humans.

SEASONAL MIGRATION AND COVID 19 IN INDIA

In December 2019, a novel Coronavirus has resulted in the outbreak of a respiratory illness known as COVID-19. Human coronavirus is the major cause of the 'common cold’. This virus has emerged from bats, adapted in other small wild mammals, and now acquired efficient human transmission. The novel disease has turned into a global outbreak. The COVID19 outbreak is upending life for families around the world. Schools, childcare centre are closed for this outbreak. Everyone is finding themselves stuck at home for most of the day due to lockdown. Emerged in 2019, the disease began threatening the health and lives of millions of people after a few weeks. These have declared a public health emergency through the whole world. Now the disease achieved a pandemic status. The goal of this research topic is to stimulate investigations on how migrants people are affected by the COVID19 emergency. Migrants are not familiar with their new environment in which they temporarily lived in. they are now facing various social, psychological, and emotional trauma in such situations. Previously they were forced to leave their native places. Now, they are facing decimations from their native places. The paper is based on secondary data sources and observations of the researchers during the lockdown phase of COVID19.

Mechanisms of SARS-CoV-2 entry into cells.

The unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. Finally, we present key outstanding questions associated with this critical process.

Genetic determinants of receptor-binding preference and zoonotic potential of H9N2 avian influenza viruses.

Receptor recognition and binding is the first step of viral infection and a key determinant of host specificity. The inability of avian influenza viruses to effectively bind human-like sialylated receptors is a major impediment to their efficient transmission in humans and pandemic capacity. Influenza H9N2 viruses are endemic in poultry across Asia and parts of Africa where they occasionally infect humans and are therefore considered viruses with zoonotic potential. We previously described H9N2 viruses, including several isolated from human zoonotic cases, showing a preference for human-like receptors. Here we take a mutagenesis approach, making viruses with single or multiple substitutions in H9 haemagglutinin and test binding to avian and human receptor analogues using biolayer interferometry. We determine the genetic basis of preferences for alternative avian receptors and for human-like receptors, describing amino acid motifs at positions 190, 226 and 227 that play a major role in determining receptor specificity, and several other residues such as 159, 188, 193, 196, 198 and 225 that play a smaller role. Furthermore, we show changes at residues 135, 137, 147, 157, 158, 184, 188, and 192 can also modulate virus receptor avidity and that substitutions that increased or decreased the net positive charge around the haemagglutinin receptor-binding site show increases and decreases in avidity, respectively. The motifs we identify as increasing preference for the human-receptor will help guide future H9N2 surveillance efforts and facilitate our understanding of the emergence of influenza viruses with increased zoonotic potential.IMPORTANCE As of 2020, over 60 infections of humans by H9N2 influenza viruses have been recorded in countries where the virus is endemic. Avian-like cellular receptors are the primary target for these viruses. However, given that human infections have been detected on an almost monthly basis since 2015, there may be a capacity for H9N2 viruses to evolve and gain the ability to target human-like cellular receptors. Here we identify molecular signatures that can cause viruses to bind human-like receptors, and we identify the molecular basis for the distinctive preference for sulphated receptors displayed by the majority of recent H9N2 viruses. This work will help guide future surveillance by providing markers that signify the emergence of viruses with enhanced zoonotic potential as well as improving understanding of the basis of influenza virus receptor-binding.

Moratorium on Research Intended To Create Novel Potential Pandemic Pathogens

Research on highly pathogenic organisms is crucial for medicine and public health, and we strongly support it. This work creates a foundation of new knowledge that provides critical insights around the world’s most deadly infectious diseases, and it can lay groundwork for the future development of new diagnostics, medicines, and vaccines. Almost all such research can be performed in ways that pose negligible or no risk of epidemic or global spread of a novel pathogen. However, research that aims to create new potential pandemic pathogens (PPP) (1)—novel microbes that combine likely human virulence with likely efficient transmission in humans—is an exception to that rule. While this research represents a tiny portion of the experimental work done in infectious disease research, it poses extraordinary potential risks to the public. Experiments that create the possibility of initiating a pandemic should be subject to a rigorous quantitative risk assessment and a search for safer alternatives before they are approved or performed. Yet a rigorous and transparent risk assessment process for this work has not yet been established. This is why we support the recently announced moratorium on funding new “gain-offunction” (GOF) experiments that enhance mammalian transmissibility or virulence in severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and influenza viruses. This realm of work roughly corresponds with the work we have termed PPP above. Because the term “gain of function” in other contexts can be used to describe techniques of scientific research that have nothing to do with the creation of novel potential pandemic pathogens, we think the term can be too broad and can mislead. Throughout this commentary, we focus on research designed to create PPP strains of influenza virus, the type of research that initially attracted attention, leading to the moratorium and for which the most discussion has already occurred. Other types of gain-of-function research on influenza and studies intended to enhance pathogenicity or transmissibility of MERS and SARS coronaviruses may or may not fit the definition of PPP research and further clarification is needed and ongoing. As we discuss near the end of this article, it will be essential to clarify the different risks and benefits entailed by different types of experiments covered by the funding pause (2). The purpose of this research funding pause is to complete “a robust and broad deliberative process . . . that results in the adoption of a new [U.S. Government] gain-of-function research policy” (3). The moratorium would stop new funding for the following:

6: Innate immune responses in human dendritic cells induced by H9N2 avian influenza virus

H9N2 influenza viruses have been circulating worldwide in multiple avian species. Occasionally H9N2 influenza viruses have been transmitted to humans. The concern is the adaptation of avian influenza viruses to efficient human transmission, which could lead to a pandemic. In this study we have examined the activation of innate immune responses in low pathogenic avian influenza (LPAI) A/HK/1073/99 (H9N2) and seasonal influenza A/Beijing/353/89 (H3N2) virus-infected human dendritic cells (DCs). In human airways and lungs the influenza virus infects epithelial cells and DCs in close proximity to epithelium which orchestrate the activation of adequate immune responses. The virus infection leads to activation of transcription factors (e.g. IRF3, IRF7 and NF-κB) which regulate the expression of proinflammary cytokines and antiviral interferons. We discovered that the H9N2 virus induced earlier interferon (IFN-α1, -β1 and -λ1) gene expression than the H3N2 virus, and the response was switch off in the late time point of H9N2 infection. Nevertheless interferon stimulated gene 15 (ISG15) and antiviral MxA protein were produced in the H9N2 virus-infected cells at least at the same level than in the H3N2 virus-infected cells. For the pro-inflammatory responses CXCL10, IL-1β and TNF-α gene expression was analyzed and it turned out that pro-inflammatory responses were stronger in H9N2 virus-infected cells than in the cells infected with the H3N2 virus. There were no differences seen in the virus-induced phosphorylation of IRF3 transcription factor or phosphorylated p38 MAP kinase between H9N2 and H3N2 viruses. All infection experiments with the H9N2 virus were carried out under biosafety level 3 (BSL-3) conditions. These results indicate that the avian influenza H9N2 virus is inducing strong but transient antiviral interferon response in human DCs. Moreover, avian H9N2 virus evoked strong pro-inflammatory response in human cells that is in line with the other avian, like H5N1 virus-induced human responses.

In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity

Acquisition of α2-6 sialoside receptor specificity by α2-3 specific highly-pathogenic avian influenza viruses (H5N1) is thought to be a prerequisite for efficient transmission in humans. By in vitro selection for binding α2-6 sialosides, we identified four variant viruses with amino acid substitutions in the hemagglutinin (S227N, D187G, E190G, and Q196R) that revealed modestly increased α2-6 and minimally decreased α2-3 binding by glycan array analysis. However, a mutant virus combining Q196R with mutations from previous pandemic viruses (Q226L and G228S) revealed predominantly α2-6 binding. Unlike the wild type H5N1, this mutant virus was transmitted by direct contact in the ferret model although not by airborne respiratory droplets. However, a reassortant virus with the mutant hemagglutinin, a human N2 neuraminidase and internal genes from an H5N1 virus was partially transmitted via respiratory droplets. The complex changes required for airborne transmissibility in ferrets suggest that extensive evolution is needed for H5N1 transmissibility in humans.

Influenza Virus Receptor Specificity: Disease and Transmission

Influenza Virus Receptor Specificity: Disease and Transmission

Avian influenza viruses in humans

Past pandemics arose from low pathogenic avian influenza (LPAI) viruses. In more recent times, highly pathogenic avian influenza (HPAI) H5N1, LPAI H9N2 and both HPAI and LPAI H7 viruses have repeatedly caused zoonotic disease in humans. Such infections did not lead to sustained human-to-human transmission. Experimental infection of human volunteers and seroepidemiological studies suggest that avian influenza viruses of other subtypes may also infect humans. Viruses of the H7 subtype appear to have a predilection to cause conjunctivitis and influenza-like illness (ILI), although HPAI H7N7 virus has also caused fatal respiratory disease. Low pathogenic H9N2 viruses have caused mild ILI and its occurrence may be under-recognised for this reason. In contrast, contemporary HPAI H5N1 viruses are exceptional in their virulence for humans and differ from human seasonal influenza viruses in their pathogenesis. Patients have a primary viral pneumonia progressing to acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome. Over 380 human cases have been confirmed to date, with an overall case fatality of 63%. The zoonotic transmission of avian influenza is a rare occurrence, butthe greater public health concern is the adaptation of such viruses to efficient human transmission, which could lead to a pandemic. A better understanding of the ecology of avian influenza viruses and the biological determinants of transmissibility and pathogenicity in humans is important for pandemic preparedness.