Paving new roads toward the advancement of broad-spectrum antiviral agents.

Broad-spectrum antivirals (BSAs) have the advantageous property of being effective against a wide range of viruses with a single drug, offering a promising therapeutic solution for the largely unmet need in treating both existing and emerging viral infections. In this review, we summarize the current strategies for the development of novel BSAs, focusing on either targeting the commonalities during the replication of multiple viruses or the systemic immunity of humans. In comparison to BSAs that target viral replication, these immuno-modulatory agents possess an expanded spectrum of antiviral activity. However, antiviral immunity is a double-edged sword, and maintaining immune homeostasis ultimately dictates the health status of hosts during viral infections. Therefore, establishing an ideal goal for immuno-modulation in antiviral interventions is crucial. Herein we propose a bionic approach for immuno-modulation inspired by mimicking bats, which possess a more robust immune system for combating viral invasions, compared to humans. In addition, we discuss an empirical approach to treat diverse viral infections using traditional Chinese medicines (TCMs), mainly through bidirectional immuno-modulation to restore the disrupted homeostasis. Advancing our understanding of both the immune system of bats and the mechanisms underlying antiviral TCMs will significantly contribute to the future development of novel BSAs.

Characterization of a mouse-adapted strain of bat severe acute respiratory syndrome-related coronavirus.

Bats carry genetically diverse severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs). Some of them utilize human angiotensin-converting enzyme 2 (hACE2) as a receptor and cannot efficiently replicate in wild-type mice. Our previous study demonstrated that the bat SARSr-CoV rRsSHC014S induces respiratory infection and lung damage in hACE2 transgenic mice but not wild-type mice. In this study, we generated a mouse-adapted strain of rRsSHC014S, which we named SMA1901, by serial passaging of wild-type virus in BALB/c mice. SMA1901 showed increased infectivity in mouse lungs and induced interstitial lung pneumonia in both young and aged mice after intranasal inoculation. Genome sequencing revealed mutations in not only the spike protein but the whole genome, which may be responsible for the enhanced pathogenicity of SMA1901 in wild-type BALB/c mice. SMA1901 induced age-related mortality similar to that observed in SARS and COVID-19. Drug testing using antibodies and antiviral molecules indicated that this mouse-adapted virus strain can be used to test prophylactic and therapeutic drug candidates against SARSr-CoVs. IMPORTANCE The genetic diversity of SARSr-CoVs in wildlife and their potential risk of cross-species infection highlights the importance of developing a powerful animal model to evaluate the antibodies and antiviral drugs. We acquired the mouse-adapted strain of a bat-origin coronavirus named SMA1901 by natural serial passaging of rRsSHC014S in BALB/c mice. The SMA1901 infection caused interstitial pneumonia and inflammatory immune responses in both young and aged BALB/c mice after intranasal inoculation. Our model exhibited age-related mortality similar to SARS and COVID-19. Therefore, our model will be of high value for investigating the pathogenesis of bat SARSr-CoVs and could serve as a prospective test platform for prophylactic and therapeutic candidates.

Natural Products and Nutrients against Different Viral Diseases: Prospects in Prevention and Treatment of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global pandemic and is posing a serious challenge to mankind. As per the current scenario, there is an urgent need for antiviral that could act as a protective and therapeutic against SARS-CoV-2. Previous studies have shown that SARS-CoV-2 is much similar to the SARS-CoV bat that occurred in 2002-03. Since it is a zoonotic virus, the exact source is still unknown, but it is believed bats may be the primary reservoir of SARS-CoV-2 through which it has been transferred to humans. In this review, we have tried to summarize some of the approaches that could be effective against SARS-CoV-2. Firstly, plants or plant-based products have been effective against different viral diseases, and secondly, plants or plant-based natural products have the minimum adverse effect. We have also highlighted a few vitamins and minerals that could be beneficial against SARS-CoV-2.

COVID-19: what has been learned and to be learned about the novel coronavirus disease.

The outbreak of Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has thus far killed over 3,000 people and infected over 80,000 in China and elsewhere in the world, resulting in catastrophe for humans. Similar to its homologous virus, SARS-CoV, which caused SARS in thousands of people in 2003, SARS-CoV-2 might also be transmitted from the bats and causes similar symptoms through a similar mechanism. However, COVID-19 has lower severity and mortality than SARS but is much more transmissive and affects more elderly individuals than youth and more men than women. In response to the rapidly increasing number of publications on the emerging disease, this article attempts to provide a timely and comprehensive review of the swiftly developing research subject. We will cover the basics about the epidemiology, etiology, virology, diagnosis, treatment, prognosis, and prevention of the disease. Although many questions still require answers, we hope that this review helps in the understanding and eradication of the threatening disease.

2019_nCoV/SARS-CoV-2: rapid classification of betacoronaviruses and identification of Traditional Chinese Medicine as potential origin of zoonotic coronaviruses.

The current outbreak of a novel severe acute respiratory syndrome-like coronavirus, 2019_nCoV (now named SARS-CoV-2), illustrated difficulties in identifying a novel coronavirus and its natural host, as the coding sequences of various Betacoronavirus species can be highly diverse. By means of whole-genome sequence comparisons, we demonstrate that the noncoding flanks of the viral genome can be used to correctly separate the recognized four betacoronavirus subspecies. The conservation would be sufficient to define target sequences that could, in theory, classify novel virus species into their subspecies. Only 253 upstream noncoding sequences of Sarbecovirus are sufficient to identify genetic similarities between species of this subgenus. Furthermore, it was investigated which bat species have commercial value in China, and would thus likely be handled for trading purposes. A number of coronavirus genomes have been published that were obtained from such bat species. These bats are used in Traditional Chinese Medicine, and their handling poses a potential risk to cause zoonotic coronavirus epidemics. SIGNIFICANCE AND IMPACT OF THE STUDY: The noncoding upstream and downstream flanks of coronavirus genomes allow for rapid classification of novel Betacoronavirus species and correct identification of genetic relationships. Although bats are the likely natural host of 2019_nCoV, the exact bat species that serves as the natural host of the virus remains as yet unknown. Chinese bat species with commercial value were identified as natural reservoirs of coronaviruses and are used in Traditional Chinese Medicine. Since their trading provides a potential risk for spreading zoonoses, a change in these practices is highly recommended.

Status of vaccine research and development of vaccines for Nipah virus.

Nipah virus (NiV) is a highly pathogenic, recently emerged paramyxovirus that has been responsible for sporadic outbreaks of respiratory and encephalitic disease in Southeast Asia. High case fatality rates have also been associated with recent outbreaks in Malaysia and Bangladesh. Although over two billion people currently live in regions in which NiV is endemic or in which the Pteropus fruit bat reservoir is commonly found, there is no approved vaccine to protect against NiV disease. This report examines the feasibility and current efforts to develop a NiV vaccine including potential hurdles for technical and regulatory assessment of candidate vaccines and the likelihood for financing.

A framework for the study of zoonotic disease emergence and its drivers: spillover of bat pathogens as a case study.

Many serious emerging zoonotic infections have recently arisen from bats, including Ebola, Marburg, SARS-coronavirus, Hendra, Nipah, and a number of rabies and rabies-related viruses, consistent with the overall observation that wildlife are an important source of emerging zoonoses for the human population. Mechanisms underlying the recognized association between ecosystem health and human health remain poorly understood and responding appropriately to the ecological, social and economic conditions that facilitate disease emergence and transmission represents a substantial societal challenge. In the context of disease emergence from wildlife, wildlife and habitat should be conserved, which in turn will preserve vital ecosystem structure and function, which has broader implications for human wellbeing and environmental sustainability, while simultaneously minimizing the spillover of pathogens from wild animals into human beings. In this review, we propose a novel framework for the holistic and interdisciplinary investigation of zoonotic disease emergence and its drivers, using the spillover of bat pathogens as a case study. This study has been developed to gain a detailed interdisciplinary understanding, and it combines cutting-edge perspectives from both natural and social sciences, linked to policy impacts on public health, land use and conservation.

Model-guided fieldwork: practical guidelines for multidisciplinary research on wildlife ecological and epidemiological dynamics.

Infectious disease ecology has recently raised its public profile beyond the scientific community due to the major threats that wildlife infections pose to biological conservation, animal welfare, human health and food security. As we start unravelling the full extent of emerging infectious diseases, there is an urgent need to facilitate multidisciplinary research in this area. Even though research in ecology has always had a strong theoretical component, cultural and technical hurdles often hamper direct collaboration between theoreticians and empiricists. Building upon our collective experience of multidisciplinary research and teaching in this area, we propose practical guidelines to help with effective integration among mathematical modelling, fieldwork and laboratory work. Modelling tools can be used at all steps of a field-based research programme, from the formulation of working hypotheses to field study design and data analysis. We illustrate our model-guided fieldwork framework with two case studies we have been conducting on wildlife infectious diseases: plague transmission in prairie dogs and lyssavirus dynamics in American and African bats. These demonstrate that mechanistic models, if properly integrated in research programmes, can provide a framework for holistic approaches to complex biological systems.

Date palm sap collection: exploring opportunities to prevent Nipah transmission.

Nipah virus (NiV) infection is a seasonal disease in Bangladesh that coincides with the date palm sap collection season. Raw date palm sap is a delicacy to drink in Bengali culture. If fruit bats that are infected with NiV gain access to the sap for drinking, they might occasionally contaminate the sap through saliva and urine. In February 2007, we conducted a qualitative study in six villages, interviewing 27 date palm sap collectors (gachhis) within the geographical area where NiV outbreaks have occurred since 2001. Gachhis reported that bats pose a challenge to successful collection of quality sap, because bats drink and defecate into the sap which markedly reduces its value. They know some methods to prevent access by bats and other pests but do not use them consistently, because of lack of time and resources. Further studies to explore the effectiveness of these methods and to motivate gachhis to invest their time and money to use them could reduce the risk of human Nipah infection in Bangladesh.

In-depth assessment of an outbreak of Nipah encephalitis with person-to-person transmission in Bangladesh: implications for prevention and control strategies.

Continued Nipah encephalitis outbreaks in Bangladesh highlight the need for preventative and control measures to reduce transmission from bats to humans and human-to-human spread. Qualitative research was conducted at the end of an encephalitis outbreak in Faridpur, Bangladesh in May 2004 and continued through December 2004. Methods included in-depth interviews with caretakers of cases, case survivors, neighbors of cases, and health providers. Results show contrasts between local and biomedical views on causal explanations and appropriate care. Social norms demanded that family members maintain physical contact with sick patients, potentially increasing the risk of human-to-human transmission. Initial treatment strategies by community members involved home remedies, and public health officials encouraged patient hospitalization. Over time, communities linked the outbreak to supernatural powers and sought care with spiritual healers. Differing popular and medical views of illness caused conflict and rejection of biomedical recommendations. Future investigators should consider local perceptions of disease and treatment when developing outbreak strategies.