Antivirals for broader coverage against human coronaviruses

Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses with a genome that is 27–31 kbases in length. Critical genes include the spike (S), envelope (E), membrane (M), nucleocapsid (N) and nine accessory open reading frames encoding for non-structural proteins (NSPs) that have multiple roles in the replication cycle and immune evasion (1). There are seven known human CoVs that most likely appeared after zoonotic transfer, the most recent being SARS-CoV-2, responsible for the COVID-19 pandemic. Antivirals that have been approved by the FDA for use against COVID-19 such as Paxlovid can target and successfully inhibit the main protease (MPro) activity of multiple human CoVs; however, alternative proteomes encoded by CoV genomes have a closer genetic similarity to each other, suggesting that antivirals could be developed now that target future CoVs. New zoonotic introductions of CoVs to humans are inevitable and unpredictable. Therefore, new antivirals are required to control not only the next human CoV outbreak but also the four common human CoVs (229E, OC43, NL63, HKU1) that circulate frequently and to contain sporadic outbreaks of the severe human CoVs (SARS-CoV, MERS and SARS-CoV-2). The current study found that emerging antiviral drugs, such as Paxlovid, could target other CoVs, but only SARS-CoV-2 is known to be targeted in vivo. Other drugs which have the potential to target other human CoVs are still within clinical trials and are not yet available for public use. Monoclonal antibody (mAb) treatment and vaccines for SARS-CoV-2 can reduce mortality and hospitalisation rates; however, they target the Spike protein whose sequence mutates frequently and drifts. Spike is also not applicable for targeting other HCoVs as these are not well-conserved sequences among human CoVs. Thus, there is a need for readily available treatments globally that target all seven human CoVs and improve the preparedness for inevitable future outbreaks. Here, we discuss antiviral research, contributing to the control of common and severe CoV replication and transmission, including the current SARS-CoV-2 outbreak. The aim was to identify common features of CoVs for antivirals, biologics and vaccines that could reduce the scientific, political, economic and public health strain caused by CoV outbreaks now and in the future

Evolutionary process of Bos taurus cattle in favourable versus unfavourable environments and its implications for genetic selection

The evolutionary processes that have enabled Bos taurus cattle to establish around the globe are at the core to the future success of livestock production. Our study focuses on the history of cattle domestication including the last 60 years of B. taurus breeding programmes in both favourable and unfavourable environments and its consequences on evolution and fitness of cattle. We discuss the emergence of ‘production diseases’ in temperate production systems and consider the evolutionary genetics of tropical adaptation in cattle and conclude that the Senepol, N'Dama, Adaptaur and Criollo breeds, among others with similar evolutionary trajectories, would possess genes capable of improving the productivity of cattle in challenging environments. Using our own experimental evidence from northern Australia, we review the evolution of the Adaptaur cattle breed which has become resistant to cattle tick. We emphasize that the knowledge of interactions between genotype, environment and management in the livestock systems will be required to generate genotypes for efficient livestock production that are both economically and environmentally sustainable. Livestock producers in the 21st century will have less reliance on infrastructure and veterinary products to alleviate environmental stress and more on the animal's ability to achieve fitness in a given production environment

The major histocompatibility complex and peptide vaccines in domestic animals

Three hypotheses are suggested to explain the phenomenon of low responsiveness in domestic animals after injection of peptide vaccines. The first hypothesis proposes involvement of MHC haplotype and the special case in livestock breeding, where inheritance of the sire's haplotype can be closely examined by injection of antigen into a large number of paternal half‐sib progeny. The second hypothesis examines the effect of repeated antigen injections in overcoming age and MHC haplotype effects and distinguishing these effects from those caused by deficiencies in the T cell repertoire. The third hypothesis concerns non‐MHC effects that influence the expression of MHC haplotype effects and enable the host to mount an effective immune response. It is suggested that the antigen recognition signal from T cell receptor/MHC interaction is amplified to a varying extent in animal populations. Deficiency in this amplification through myeloid cell or cytokine responses may be yet another factor limiting immune responsiveness

High and low responsiveness to vaccines in farm animals

Low responsiveness in some farm Animals is emerging as a problem in the application of newly developed vaccines which operate at skin surfaces and mucous membranes. Breeding for resistance to specific diseases seems to be associated with breeding for specific immune responsiveness in farm Animals and very likely this involves selection for major histocompatibility complex (MHC) haplotype. However, other factors contribute to low responsiveness and these include poor nutrition, sire effects, antigenic competition and inadequate effector mechanisms. The future of newly developed vaccines will rest on the solution to the low responder problem, and once solved, the application of these vaccines will be fully utilized for disease control in farm Animals

The use of embryo genotyping in the propagation of genes involved in the immune response

Multiple ovulation and embryo transfer (MOET) now enables researchers to produce identical twin animals, to obtain progeny from pre-pubertal females and to obtain more offspring from valuable animals. MOET and sexed semen have produced genetic progress of up to 60% of milk production. The oestrous cycles of animals are synchronized with progestagens before superovulation with gonadal hormones, pregnant mare serum gonadotrophin and follicle stimulating hormone. Surgical, non-surgical and laparoscopic methods are applied to recover and transfer embryos. Sexing and genotyping of the pre-implantation embryos is a key step in improving the management and breeding programmes for livestock, as well as in the human for the prenatal diagnosis of genetic disorders. Several serological and physiological methods have been used to determine the sex of the pre-implantation embryos; none has had satisfactory results in terms of time and accuracy. Sexing by polymerase chain reaction (PCR) using male-specific chromosome sequences alone or with female-specific chromosomal DNA probes simultaneously has been sufficient to identify the sex of the embryos with 100% accuracy. However, caution should be taken against sources of the contamination. The MHC class I, class II and background genes have been implicated in resistance to internal parasites in animals. Biotechnological methods such as screening of embryos prior to transfer using PCR and primer extension pre-amplification have already made it possible to, detect transgenic or genetically disordered embryos and could be applied to select those embryos bearing immunological genotypes of interest, such as resistance to internal parasites. Ultimately, cloning and nuclear transplantation would provide the possibility of isolating these resistance genes and to transfer them to livestock pre-implantation embryos to propagate these desirable traits

The immunogenetics of resistance toTrichostrongylus colubriformis and Haemonchus contortus parasites in sheep

Three possible immunogenetic markers for resistance to intestinal parasitesin sheep have been studied. Allotypes of the major histocompatibility complex (MHC) of the sheep have been investigated as markers, using serological typing or gene probes, for associations between allotypes and resistance to parasites in selected high responder and low responder lines of sheep. Only the serologically-determined class I ovine leucocyte antigen (OLA) types SY 1a and SY 1b have been found to be consistently associated with increased resistance to Trichostrongylus colubriformis, but this association has not extended to the immunological distinct Haemonchus contortus parasite. Gene probes of the sheep DRB, DQB and DQA MHC class II loci have detected animals with increased susceptibility to T. colubriformis. Eosinophilia was investigated as a marker and found to be associated with increased resistance to parasites in lines of Australian Merinos and New Zealand Romneys selected for resistance on the basis of low faecal egg count. Blood eosinophilia was distinct from eosinophil infiltration of the gut which was poorly associated with resistance. The mechanism of parasite resistance appeared to involve the release of vasoactive amines and leukotrienes into intestinal mucus, since the selected high responder sheep to T. colubriformis and H. contortus had significantly increased amounts of these agents in their gut mucus, compared with selected low responder or random-bred sheep. Antibodies to T. colubriformis and H. contortus have also been used as markers to select high responder sire groups of lambs in contact with the parasites, for the first time, at weaning. This assay had the advantage of detecting distinct antigens for the two parasites, which would allow resistance to the species of parasite to be selected in the lambs. Vaccines have been developed against H. contortus using 'novel' gut antigens from the parasite, but variable responsiveness of the host sheep seemed to result in varying degrees of protection which were stimulated by these vaccines