Abstract: Simian foamy virus (SFV) is a retrovirus that infects primates, including American primates (AP), but epidemiological studies are often limited to captive animals. The state of Rio de Janeiro (RJ) is home to an endemic AP species, Leontopithecus rosalia, and an invasive species, Leontopithecus chrysomelas, both endangered. This study assessed the molecular prevalence of SFV in these species. Genomic DNA was extracted from 48 oral swab samples of L. chrysomelas (Niterói/RJ) and 102 of L. rosalia (Silva Jardim/RJ). qPCR was performed to diagnose and evaluate proviral load (pVL). SFV prevalence was 23% in L. chrysomelas and 33% in L. rosalia. No age-related differences were observed, but L. rosalia showed a higher average pVL (3.27 log10/10⁶ cells) compared to L. chrysomelas (3.03 log10/10⁶ cells) (p=0.005). The viral sequence of L. rosalia clustered within a monophyletic SFVlro clade, distinct from two SFVlchrysom lineages. Origin of SFVlro dates back to 79.6 thousands of years ago. This was the first study to determine the molecular prevalence of SFV in free-living populations of Leontopithecus, and may be of great importance for elucidating the complex evolutionary history of SFV in AP.

Abstract: Porcine Epidemic Diarrhea Virus (PEDV) was introduced in the United States (U.S.) in 2013, spreading rapidly and leading to economic losses. Two strains, S-INDEL and non-S-INDEL, are present in the U.S. We analyzed 313 genomes and 556 Spike protein sequences generated since its introduction. PEDV case numbers were highest during the first two years after its introduction (epidemic phase), then declined and stabilized in the following years (endemic phase). Sequence availability was higher during the initial epidemic phase. Our results suggest non-S-INDEL strain is the predominant strain in U.S. The non-S-INDEL strain exhibits a nucleotide identity percentage above 97.6%. Most non-S-INDEL sequences sampled after 2017 clustered into two sub-clades. No descendants derived from other clades present in the epidemic period were identified in the contemporary data, suggesting that these clades are no longer circulating in the U.S. The two clades currently circulating are restricted to two respective geographic regions and our results suggest limited inter-regional spread. This insight helps determine the risk of re-introduction of PEDV if it were regionally eliminated. Continued molecular surveillance is key to confirming the extinction of older clades, mapping the distribution and spread of recent clades, and understanding PEDV's evolutionary diversification..

Abstract: Influenza A virus (IAV) infections continue to threaten public health. Current strategies, such as vaccines and antiviral drugs, are limited due to time-consuming development and drug-resistant strains. Therefore, new effective treatments are needed. Here, virus-supportive cellular factors are promising drug targets, and encapsulation of candidate substances in PLGA nanoparticles (NPs) is intended to improve their bioavailability. This study investigates the potential of the indirubin derivative 6BIGOE, a GSK-3β inhibitor, for its potential to regulate IAV replication in vitro. The effects of 6BIGOE-loaded PLGA NPs on cell metabolism were assessed by MTT and LDH assays in A549 and Calu-3 cells. Viral replication and spread were monitored in various IAV-infected cell lines in absence and presence of free and 6BIGOE-loaded PLGA NPs via plaque assays and Western blot analysis. Encapsulation of 6BIGOE in PLGA NPs resulted in reduced negative side effects on cell viability while maintaining antiviral efficacy. Both encapsulated and free 6BIGOE exhibited antiviral activity, potentially through GSK-3β inhibition and disruption of key signaling pathways required for viral replication. The data indicate 6BIGOE, particularly after encapsulation in NPs, as a potential candidate for further investigation and development as an antiviral agent to treat IAV infections.

Abstract: SARS-CoV-2 high transmission and genomic mutations result in the emergence of new variants that impact COVID-19 vaccine efficacy and virus transmission by evading the host immune system. Wastewater-based epidemiology is an effective approach to monitor SARS-CoV-2 variants circulation in the population but is a challenge due to the presence of reaction inhibitors and the low concentrations of SARS-CoV-2 in this environment. Here, we aimed to improve SARS-CoV-2 variant detection in wastewater by employing nested PCR followed by next-generation sequencing (NGS) of small amplicons of the S gene. Eight SARS-CoV-2 wastewater samples from Alegria Wastewater Treatment Plant, in Rio de Janeiro, Brazil, were collected monthly from February to September 2021. Samples were submitted to virus concentration, RNA extraction and nested PCR followed by NGS. The small amplicons were used to prepare libraries for sequencing without the need to perform any fragmentation step. We identified and calculated the frequencies of 29 mutations matching the Alpha, Beta, Gamma, Delta, Omicron and P.2 variants. Omicron matching-mutations were detected before the lineage was classified as a variant of concern. SARS-CoV-2 wastewater sequences clustered with SARS-CoV-2 variants detected in clinical samples that circulated in 2021 in Rio de Janeiro. We show that sequencing of selected small amplicons of SARS-CoV-2 S gene allows the identification of SARS-CoV-2 variants matching-mutations and their frequencies calculation. This approach may be expanded using customizing primers for additional genomic regions, in order to differentiate current variants. Approaches that allow us to learn how variants emerge and how they relate to clinical outcomes are crucial for our understanding of the dynamics of virus variants circulation, providing valuable data for public health management.

Abstract: Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe or fatal infections in humans and is geographically widespread. The virus has coevolved with its tick vectors, establishing persistent infections critical to its transmission. This study explores the mechanisms underpinning these persistent infections, using tick cell lines and Hazara virus (HAZV) as a biosafety level 2 (BSL-2) model for CCHFV. Initially, an RT-qPCR protocol was developed to detect HAZV in tick cells. The study then focused on the production of virus-derived DNA (vDNAs) by tick cells as a defensive response to infection. These vDNAs regulate viral particle production, enabling tick cells to maintain viability and establish persistent infections. Experiments characterized vDNAs production, viral titers, and subcellular localization, and examined the effect of the reverse transcriptase inhibitor azidothymidine triphosphate (AZT). Results showed that all tested tick cell lines supported HAZV replication, achieving persistent infections without cytopathic effects. vDNAs was detected in both the cytoplasm and nucleus, and its formation was dependent on HAZV infection. Importantly, vDNAs presence was linked to infection persistence; cells treated with AZT exhibited a marked reduction in vDNAs production and an associated increase in viral particle production, which correlated with higher cell death. These findings underscore the critical role of vDNAs in balancing viral replication and promoting long-term cell survival in tick cells, highlighting their importance in the coevolution of tick-borne viruses and their vectors.

Abstract: It has been widely known that the Pseudorabies virus (PRV) presents a significant health risk to swine, inflicting considerable economic losses in breeding industry, but those basic function about this disease still keeps unknown. For further understanding its potentiality, the antiviral potential of extracts from five plants against PRV was investigated in vitro. Notably, Aconitum tanguticum and Belamcanda chinensis demonstrated significant inhibition through distinct antiviral mechanisms. Aconitum tanguticum exhibited dose-dependent antiviral activity, significantly reducing viral RNA synthesis, protein expression, and the production of infectious progeny in infected Vero cells. Its primary mechanism involves direct viral binding, leading to substantial reduction in viral titers and a 90% inhibition rate in Vero cells with a concentration of 10 mg/mL. Conversely, Belamcanda chinensis interferes with host cell processes, showing enhanced efficacy post-PRV infection. Both agents effectively protected mice by prolonging survival, alleviating clinical symptoms and histopathological damage in their major organs, and reducing viral loads in lungs and livers. These findings dig out the potential of Aconitum tanguticum and Belamcanda chinensis as therapeutic agents against PRV infections.

Abstract:

HIV-1 integrase (IN), an essential viral protein that catalyzes integration, also influences non-integration functions such as particle production and morphogenesis. The mechanism by which non-integration functions is mediated is not completely understood. Several factors influence this non-integration function including ability of IN to bind to viral RNA. INI1/SMARCB1 is an integrase binding host factor that influences HIV-1 replication at multiple stages, including particle production and particle morphogenesis. IN mutants defective for binding to INI1 are also defective for particle morphogenesis, similar to RNA-binding-defective IN mutants. Studies have indicated that the highly conserved Repeat (Rpt)1, the IN-binding domain of INI1, structurally mimics TAR RNA and that the Rpt1 and TAR RNA compete for binding to IN. Based on the RNA mimicry, we propose that INI1 may function as a “place-holder” for viral RNA to facilitate proper ribonucleoprotein complex formation required during the assembly and particle morphogenesis of the HIV-1 virus. These studies suggest that drugs that target IN/INI1 interaction may lead to dual inhibition of both IN/INI1 and IN/RNA interactions to curb HIV-1 replication.

Abstract: Influenza A viruses (IAVs) evolve rapidly, exhibit zoonotic potential, and frequently adapt to new hosts, often establishing long-term reservoirs. Despite advancements in genetic sequencing and phylogenetic classification, current influenza nomenclature systems remain static, failing to capture evolving epidemiological patterns. This rigidity has led to misinterpretations in public health responses, economic disruptions, and confusion in scientific communication. Existing nomenclature does not adequately reflect real-time transmission dynamics or host adaptations, limiting its usefulness for public health management. The misnomer "swine flu" for the 2009 H1N1 pandemic (A(H1N1)pdm09) has created undue public confusion and potential stigma despite no direct pig-to-human transmission. This review proposes a real-time, transmission-informed nomenclature system that prioritizes host adaptation and sustained transmissibility (R0) to align influenza classification with epidemiological realities and risk management. Through case studies of H1N1pdm09, H5N1, and H7N9, alongside a historical overview of influenza naming, we demonstrate the advantages of integrating transmission dynamics into naming conventions. Additionally, we discuss how a transmission-based framework can enhance public health responses and propose research and surveillance strategies to support its implementation. Adopting a real-time, transmission-informed approach will improve pandemic preparedness, strengthen global surveillance, and enhance influenza classification for scientists, policymakers, and public health agencies.

Abstract: African Swine Fever (ASF) outbreak was first recorded in the Philippines in July 2019. Since then, the disease has spread across provinces in Luzon, Visayas, and Mindanao causing severe economic consequences for the country’s swine industry. . Here, we report the genome sequencing of ASF virus strains from outbreaks in several provinces of the Philippines between 2021 to 2023, using a long-read tiled amplicon sequencing approach. The coding-complete genomes generated ranged from 187,609 to 189,540 bp in length, with GC content of 38.4% to 38.5%. Notably, a strain from Bataan province had a 1.9-kb deletion at the 5’-end affecting several coding regions. The strains were characterized using 13 genes and regions, namely, B646L gene, CD2v serogroup, central variable region (CVR) of B602L gene, intergenic region (IGR) between I73R and I329L genes, IGR between A179L and A137R, O174L, K145R, Bt/Sj, J268L, ECO2, and multigene family (MGF) 505-5R, and MGF 505-9R and 10R. The ASFV strains were most related to Asian and European p72 genotype II strains. Genetic profiling provides valuable information on the diversity of local strains of ASFV in the Philippines, which are useful for epidemiology, diagnostics, and in vaccine development.

Abstract: The cellular enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is required for NF-κB to activate inflammatory and immune response gene expression. NF-κB is also an important transcription factor in HIV-1 gene expression during active replication and latency reactivation. Therefore, enhancing NF-κB signaling is an alternative for HIV-1 latency reactivation, but significant systemic side effects related to the NF-κB role in inflammatory and immune responses are predictable. To verify this prediction, we determined whether PARP-1 is required in NF-κB-dependent HIV-1 gene expression in a human CD4+ T lymphoblastoid cell line (SUP-T1) and HEK 293T cells. Our findings indicated that PARP-1 knockout does not impair HIV-1 infection or gene expression. Specifically, NF-κB-dependent HIV-1 gene expression was not impaired by PARP-1 deficiency, highlighting an important transcriptional regulatory difference between HIV-1 and inflammatory and immune activation genes. Our findings define a negligible role of PARP-1 in HIV-1 gene expression, suggesting that PARP-1 antagonism could ameliorate the expected inflammatory response with latency-reactivating agents that act through the NF-κB signaling pathway.

Abstract:

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has undergone significant mutations since its emergence, resulting in a variety of antigenic variants. One of these variants is Omicron. Methods: In this study, the blood samples from 98 patients with acute coronavirus disease-19 (COVID-19) who were hospitalized during the initial SARS-CoV2 wave and the onset of Omicron infection in 2021 were analyzed. We used high-resolution melting (HRM) of PCR products to analyze RNA extracted from two clinical samples collected in July and November of 2021 from patients infected with the SARS-COV-2 virus. Results: HRM-analysis detected a characteristic deletion in the N-protein RNA of the virus isolated from November 2021 that is associated with the Omicron variant. Elevated levels of C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR), and interleukin-6 (IL-6) were observed in patients during both initial wave of COVID-19 and 2021 hospitalization. Additionally, complement levels were more frequently detected at the start of hospitalization during the second wave. IgG and IgM antibodies to SARS-CoV-2 were detected more often at the beginning of hospitalization during the second wave of COVID-19. During both outbreaks, an increase in hemagglutinin-inhibiting (HI) antibodies against Influenza A and B was observed in paired blood specimens from moderate to severe COVID-19 patients. Conclusions: Patients admitted during both waves of COVID-19 showed a significant rise in several inflammatory markers, suggesting that Omicron triggers significant inflammatory responses. The rapid formation of IgM and IgG in Omicron patients may indicate a faster immune response due to memory B cell formation after previous infections or vaccinations. Seasonal flu may negatively impact the clinical course of coronavirus infections. Further research is needed to determine if clinical presentation and laboratory parameters change in response to variations in the SARS-CoV virus in breakthrough cases and in patients with post-COVID syndrome.

Abstract:

Hepatocellular carcinoma (HCC) is a significant burden on global public health, being one of the main causes of cancer mortality worldwide. This type of cancer has been closely linked to viral and environmental factors, particularly hepatitis B virus (HBV) infection and exposure to aflatoxins, produced by fungi of the genus Aspergillus. Aflatoxins are known carcinogens found in contaminated foods, such as grains and nuts. In the presence of chronic HBV infection, they can function as cofactors in liver carcinogenesis. The synergistic interaction between HBV and aflatoxins is crucial for understanding the molecular complexity of HCC. Multiple studies have shown how the simultaneous presence of these carcinogens significantly increases the risk of developing HCC. The complexity of these mechanisms highlights the urgent need for targeted preventive and therapeutic strategies, ranging from improvements in food safety and aflatoxin regulation to widespread HBV vaccination in high-prevalence areas. Understanding the molecular interactions between these environmental and viral factors is crucial not only for the diagnosis and treatment of HCC, but also for the effective implementation of public health policies that re-duce the global burden of this devastating liver disease. A multifactorial approach is essential to effectively address the increasing prevalence of HCC worldwide and improve health outcomes for affected populations.

Abstract:

One of the main threats for the survival of the Iberian lynx are infectious diseases. Feline parvo-viruses cause an often fatal disease in cats and have been isolated from different species of Felidae and other carnivores. The present study is the first description of a parvoviral sequence isolated from the brain of an Iberian lynx which had died four weeks after been transferred to a quarantine centre from a hunting estate in Castilla-La-Mancha (southern border of the Iberian plateau). Four days prior to death he had developed anorexia and muscle weakness. The nucleotide sequence, 4,589 nt long (GenBank PP781551), was most proximal to that isolated from a Eurasian badger in Italy but showed also great homology with others from cats and other carnivores isolated in Spain and Italy, including that from a cat sequenced by us to elucidate the origin of the infection, which has not been clarified. The phylogenetic analysis of the capsid protein, VP2, which determines tropism and host range, confirmed that the lynx sequence was most proximal to feline than to canine parvoviruses, and was thus classified as Protoparvovirus carnivoran 1. More studies, in-cluding serology, are needed to understand the pathogenesis of this infection.

Abstract: An increase in IgG4 levels is typically associated with immunological tolerance states and develops after prolonged exposure to antigens. Accordingly, IgG4 is considered an anti-inflammatory antibody with a limited ability to trigger efficient immune responses. Additionally, IgG4 reduces allergic reactions by blocking immunoglobulin E (IgE) activity. In the case of COVID-19, it has been reported that the repeated administration of some vaccines induces high IgG4 levels. The latest research data has revealed a surprising IgE anti-receptor binding domain response after both natural infection and several SARS-CoV-2 vaccines. The presence of IgG4 and IgE in COVID-19 disease suggests that the virus may induce an “allergic-like” response to evade immune surveillance, leading to a shift from Th1 to Th2, which promotes tolerance to the virus and potentially contributes to chronic infection. The spike protein from vaccines could also induce such a response. Interestingly, "allergen-like" epitopes and IgE responses have been reported for other viruses, such as HIV and respiratory syncytial virus (RSV). The impact of this viral-induced tolerance will be discussed, concerning the protective efficacy of vaccines.

Abstract:

The emergence of an another bluetongue virus serotype BTV-3 has been causing great losses in animal farming in Europe since fall 2023. The virus spreads faster than the epidemic BTV-8, which appeared on the continent nine years earlier. The study describes first case of BTV-3 in Poland detected in European bison (Bison bonasus), just approx. 15 km from the German-Polish border. The animal suffered from severe and fatal hemorrhagic disease. The symptoms included respiratory problems, bloody diarrhea and rapidly progressive cachexia. In addition to confirmation of BTV-3 infection in the blood and spleen of the animal, the virus was also detected in one of pool of blood-fed Culicoides punctatus caught near the enclosure two weeks after the death of European bison. This is the first evidence of BTV-3 detection in C. punctatus what suggests vector competency for this serotype. Phylogenetic analysis based on the segment 2 of the virus revealed homology of Polish isolate to the BTV-3 strains circulating in the Netherlands, Germany and Portugal, and slightly lower similarity the BTV-3 strains detected in sheep in Sardinia (Italy) in 2018 and in Tunisia in November 2016. Retrospective serosurvey of the exposure to BTV in thirteen other European bison populations widespread in the country indicated that the observed case at the Wolin National Park was the first BTV-3 to be detected in Poland.

Abstract: Avian reovirus (ARV) is an important pathogen of poultry, yet the molecular responses to ARV across cell-types remain unknown. The present study explores the differential transcriptomic responses to ARV S1133 infection in three cell types, i.e. chicken embryo kidney (CEK), chicken embryo liver (CELi), and macrophage-derived cells (HD11) at 6, 12 and 24 hours post-inoculation (hpi). CELi cells exhibited the highest viral replication rates at all timepoints, with maximal titer observed at 24 hpi, whereas HD11 cells showed limited viral replication but extensive host transcriptional activity. Differential gene expression analysis revealed that HD11 cells, despite the lower viral load, presented the most pronounced transcriptional changes. CEK cells demonstrated a unique activation of immune-related pathways, specifically those related to lymphocyte chemotaxis and type II interferon response. CELi cells showed upregulation of expression of genes involved in defense against viruses. Protein-protein interaction (PPI) analysis identified key antiviral genes, including IFI6, OASL, RSAD2, SAMD9L, and MX1, as central nodes. In CELi, significant alternative splicing events were observed in transcripts of several genes, including those implicated in immunity. Taken together, results indicate that inoculation of ARV entailed cell-type and time-dependent viral replication and triggered transcriptional activity linked with unique but functionally interconnected pathways.

Abstract: Porcine reproductive and respiratory syndrome virus (PRRSV) poses significant challenges to swine production due to its rapid generation of genetic variants and its ability to suppress antiviral interferon (IFN) responses, leading to ineffective immunity. To address this, we developed a replication-competent PRRSV modified live vaccine (MLV) candidate, IFNmix, engineered to co-express three type I IFN subclasses (IFNα, IFNβ, IFNδ) to enhance antiviral immunity. In two independent experiments, we compared IFNmix to two commercial PRRSV MLV vaccines. Pigs vaccinated with IFNmix exhibited similar anti-PRRSV antibody development, serum viral loads, lung lesions, and cytokine responses post-challenge with the virulent NADC34 strain. IFNmix induced comparable or lower body temperatures and weight gain patterns relative to commercial vaccines. While IFNmix showed viral load reduction compared to a commercial vaccine especially during the early phase (Day 7-14 post challenges), it demonstrated similar efficacy in controlling PRRSV replication and lung pathology. These findings suggest that IFNmix, by expressing multiple IFNs, can potentially enhance innate and adaptive immune responses, offering a promising approach to improving PRRSV vaccine efficacy. Further studies are needed to evaluate IFNmix against a broader range of PRRSV strains and to optimize its attenuation and immunogenicity.

Abstract: Avian reovirus (ARV) infections significantly impact the global poultry industry, but host responses across infection models remain poorly characterized. Using specific-pathogen-free chicken embryos, this study examined tissue-specific transcriptomic changes following in ovo inoculation with two doses of ARV S1133 at embryonic day 18. Quantitative PCR confirmed dose- and time-dependent viral replication, with the liver exhibiting the highest viral load at 24 hours post-inoculation (hpi), whereas the kidney, intestine, and bursa were only positive at 48 hpi with the higher viral dose. Transcriptomic profiling revealed the intestine mounted an extensive gene expression response, implicating early immune activation. Liver samples demonstrated strong upregulation of antiviral pathways, including interferon signaling and viral replication inhibition, while kidneys and intestines were enriched for coagulation and wound healing pathways. The bursae exhibited minimal immunity-related responses, suggesting insufficient maturation. Functional analyses confirmed tissue-specific immune and metabolic adaptations to infection. These findings indicate that ARV replication efficiency and host molecular responses are dose-, tissue-, and time-dependent. Notably, intestinal responses suggest preemptive immune engagement, while hepatic antiviral mechanisms may play a critical role in restricting viral spread. This study establishes foundational knowledge of host molecular responses to ARV in late-stage embryos, with implications for in ovo vaccination and early immunity.

Abstract: More than three decades have passed since adult T-cell leukemia/lymphoma (ATL) was first identified as a distinct disease in Japan. During this time, researchers discovered its causative agent—the human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 infection has a significant global prevalence, affecting an estimated 5–10 million individuals worldwide. In this review, we provide a comprehensive overview of HTLV-1 persistence, latency, replication, and oncogenesis, with a particular focus on the roles of viral proteins such as Tax, HBZ, Rex, p30, p12, and p8. Understanding these mechanisms is essential for developing effective therapeutic strategies against HTLV-1-associated diseases, including ATL. Additionally, we explore current treatment strategies for ATL, including conventional chemotherapy, allogeneic hematopoietic cell transplantation, and epigenetic therapies. Gaining deeper insights into HTLV-1 pathogenesis, its molecular drivers and the existing therapeutic approaches can pave the way for more refined and innovative strategies to combat HTLV-1-associated malignancies.

Abstract:

The severe acquired respiratory coronavirus–2 (SARS–CoV-2) infection has initiated both acute and chronic COVID–19 disease between 2020 and 2023, currently evolving with other homologous prior coronavirus strains of the Nidoviridae order, which encompasses other prevalent alpha/ beta coronaviruses, but also the Middle East Respiratory Syndrome (MERS-CoV) and SARS-CoV-1, with recent SARS–CoV–2 variants, increasing demands for effective immunogens and therapeutic approaches that will reduce global disease burden and further infection from SARS–CoV-2 affected individuals that may experience post acute sequelae (PASC) or “Long COVID”. Following a worldwide programme of prophylactic vaccination, there is still a dilemma in the efforts to find prophylactic and early therapeutic approaches that would treat novel SARS-CoV-2 variants and prevent future epidemics or pandemics within host human and animal populations, where zoonotic or cross species transfer naturally occurs. Concerns about viral immune escape intersect at a specific point; a gained evolutionary ability of several viruses to co–infect and compete against previous scientific advances since 1796 that remain undetected or asymptomatic during the early stages of infection progressing to symptomatic and severe disease via the double methylation of the 5' end of eukaryotic DNA or RNA-based viral genomes, the 7-MeGpppA2’-O-Me cap, and its double methylation capping process is performed by the activated viral 2’ - O - Methyltransferase (MTase) enzyme, a complex of two viral non-structural proteins (NSPs) joined together through an activation process (NSP10/16) and by N7-Methyltransferase (N7-MTase/NSP14), respectively. Moreover, it was discovered that polymorphic viruses translate NSP1, which prevents the activation of various Pattern Recognition Receptors (PRRs), and consequently, detection of Pathogen-Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs) alike. NSP1 also silences important interferon-encoding genes (INGs) and interferon-stimulated genes (ISGs), is signalled in a paracrine manner to neighbouring cells, and that induces the apoptosis of host cells, inducing an effect of “trace erase” effect and making the viral infection as immunologically “invisible” as possible during the initial, key stages of viral replication and distribution, all such mechanisms occurring independently of the viruses in cause. Another important viral NSP is NSP14, as it plays two functional roles that are independent of each other; to produce new viral genetic material for the purpose of maintaining the validity of the viral genome as well, and not just transfer a methyl group to the 5’ end of the viral genome. Other viral NSPs share a role with NSP1, 10, 14 and 16 in directly suppressing the activation of PRRs and ISGs, and all such viral proteins help the virus in its process of self-camouflaging against first- and second-line immunity, thereby often severely impacting the quality of the produced adaptive immune responses. The outcome of all such phenomena is the sharp decrease in the host Type I and Type III interferons' (IFNs) rate of synthesis by the host cells, that would usually occur and affect homeostatic cellular pathways, resulting in further viral replication and induced apoptosis. Nonetheless, effects of microbial immune evasion during the development of other viral or carcinogenic pathologies are not widely known. In short, polymorphic viruses developed a proportionate evolutionary response against developed adaptive immune responses, by currently relying on gaps mostly situated in the natural immune system in their process of molecular self-camouflaging. Scientists developed numerous approaches of early treatment that generally showed good success rates and fewer risks of adverse events, and the still early present stages of COVID-19 research should also be taken into consideration whilst filtering for the most appropriate solutions. For example, the administration of recombinant human interferons I and III into the nasal mucosa cellular layer, as key mediators of anti–viral activity, can simulate intracellular infection and stimulate cellular activity in a timely manner, training the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Another example could involve the treatment of natural and adaptive lymphocytes with a low dose of IFNs I and possibly III, prior to their insertion into the host lymphatic system, possibly alongside additional recruitment of plasmacytoid dendritic cells (pDCs) as further interferon “factories”, all with the purpose of early infection management. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. It is until the scientific community realises this potentially crucial aspect that large proportions of the world population will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades, evidenced with dengue fever and more recently, monkeypox and possibly avian flu. Of note, it has been indicated that IFN I and / or III display significant immunising, early therapeutic and clinical disease onset-attenuating effects for many other microbial evoked diseases, as well as for a number of oncological diseases. Microbial agents could undergo loss-of-function research upon genes responsible for inducing clinical illness whilst keeping genes responsible for microbial reproduction and transmission at least generally as functional, CRISPR-Cas9 genome editing to have genes encoding proteins suppressive of the host interferon system eliminated prior to human genes encoding Pattern Recognition Receptor activator or agonist proteins, such as outer membrane proteins of Neisseria meningitidis, as well as Type I, Type III and possibly even Type IV Interferons and various ISGs inserted into the microbial genome. Such an approach would be based upon the model of editing genes of harmless bacteria to transform such them into “producers” and “distributors” of human insulin, and could turn several microbial agents into clinically harmless, transmissible “factories” for various key elements of the host interferon system, potentially placing such microbes into a reverse evolutionary path that would be deemed as “natural de-selection”, visibly reducing the average burden of disease and metabolic stresses, which in turn could gradually increase average human and animal lifespans worldwide.