Molecular systems of emerging viruses: replication, host immune evasion, cross-species adaptation and precision countermeasures

1 Introduction

Emerging viral diseases arise when a virus acquires, exposes or exploits a combination of ecological opportunity and molecular compatibility that permits infection in a new host or altered transmission in an existing host. This process is rarely controlled by a single mutation. Instead, it depends on a cascade of events: reservoir shedding, host contact, receptor engagement, protease activation, genome replication, innate immune antagonism, tissue tropism, viral shedding and population-level spread (1–3). The same cascade explains why a virus may be detected frequently at the animal-human interface yet fail to establish sustained human transmission, whereas another virus with modest ecological exposure may spread explosively once critical within-host barriers are crossed (4).

The contemporary virological landscape reinforces the need for a molecularly informed approach. Coronaviruses, filoviruses, influenza viruses, flaviviruses, alphaviruses, henipaviruses, arenaviruses, orthopoxviruses and other RNA and DNA viral families have demonstrated the capacity to emerge or re-emerge under changing ecological and social conditions (5–8). A family-level strategy is particularly important because a single named pathogen often represents only one member of a broader evolutionary space. The WHO R&D Blueprint has therefore moved towards pathogen-family and prototype-pathogen thinking, a shift that encourages transferable knowledge, platform countermeasures and faster deployment during unknown “Disease X” events.

Molecular mechanisms of emergence are best understood as linked gates. Viral surface proteins determine attachment and entry, but compatibility between viral glycoproteins and host receptors does not guarantee productive infection. Intracellular host factors, polymerase activity, codon usage, replication organelles, interferon sensitivity and immune evasion proteins collectively determine whether progeny virus can be produced and transmitted (9–13). For SARS-CoV-2, the convergence of ACE2 engagement, spike priming, furin-site biology, replication-complex efficiency and immune evasion created a biologically favourable foundation for pandemic expansion (14–18).

Genome evolution further complicates control. Point mutation, recombination, reassortment, gene gain or loss, and host-edited hypermutation can alter antigenicity, tropism, diagnostic sensitivity and drug susceptibility. SARS-CoV-2 variants illustrate how antigenic escape, transmissibility and immune evasion can be selected at population scale (7, 19–24). Influenza A viruses add reassortment and animal reservoirs to this evolutionary repertoire, while orthopoxviruses show that large DNA viruses can still undergo epidemiologically meaningful evolution under transmission pressure (8, 25, 26).

The management of emerging viruses is increasingly driven by the convergence of genomics, structural biology, immunology and computational sciences. Genomic epidemiology has transformed outbreak reconstruction for Ebola, Zika, yellow fever, SARS-CoV-2 and mpox by linking sequence data to transmission dynamics (27–31). CRISPR-based diagnostics and metagenomic next-generation sequencing extend detection capacity beyond conventional assays, while mRNA, viral-vector and protein-subunit vaccine platforms provide adaptable prevention pipelines (32–38).

Recent reviews commonly discuss molecular pathogenesis, individual virus families or pandemic preparedness as separate topics. The distinctive contribution here is an evidence-graded systems framework that links family-level molecular gates to operational decisions: which signal should trigger phenotyping, diagnostic revalidation, surveillance escalation, prototype countermeasure testing or a clinical study. It also compares heavily studied respiratory viruses with neglected haemorrhagic and vector-borne threats, thereby exposing where apparent knowledge reflects publication density rather than preparedness maturity. Figure 1 presents this original sequence-to-decision architecture.

2 Materials and methods

This paper was designed as a narrative, mechanism-centred review rather than a systematic review or meta-analysis. PubMed/MEDLINE, PubMed Central, Scopus and Web of Science were searched for English-language literature published from 1 January 2017 to 28 July 2026. Supplementary targeted searches were performed on publisher platforms (Springer Nature, Elsevier/ScienceDirect, MDPI, ASM and Frontiers) and authoritative WHO materials. Search concepts combined emerging or re-emerging virus with replication, entry receptor, protease, assembly, immune evasion, host switching, zoonotic spillover, genomic surveillance, metagenomics, CRISPR diagnostics, artificial intelligence, vaccine platform, monoclonal antibody, antiviral and One Health.

Reference lists of high-relevance reviews were also examined.

Eligible sources were peer-reviewed primary studies, high-quality reviews, clinical trials and authoritative technical frameworks that contributed mechanistic, comparative or translational evidence. We excluded non-peer-reviewed commentary, duplicate reports, papers without sufficient methodological detail, and sources focused on procedural laboratory manipulation without relevance to risk interpretation or management. Seventy-five publications were retained in the final synthesis. Literature quality was appraised narratively using relevance, methodological transparency, directness of evidence, consistency across study types and external validation; the SANRA domains informed reporting quality for this narrative review (39). No pooled effect sizes or formal risk-of-bias scores were calculated. Conflicting findings and inference limits were retained rather than resolved by citation count.

3 Results

3.1 Priority virus families and the molecular logic of emergence

The highest-risk emerging viruses cluster in families where ecological exposure intersects with molecular plasticity. Coronaviridae combine large RNA genomes, recombination, broad mammalian reservoirs and spike-mediated receptor flexibility. Orthomyxoviridae possess segmented genomes that permit reassortment, enabling rapid antigenic and host-range shifts. Filoviridae and Paramyxoviridae have non-segmented negative-sense RNA genomes, but their glycoproteins and immune-antagonist proteins facilitate severe disease in susceptible hosts. Flaviviridae and Togaviridae are shaped by vector ecology, climate-sensitive transmission and envelope-protein adaptation (3, 5, 40).

The family-level view is not simply taxonomic. It provides a practical map for prototype-pathogen research. For instance, studying one coronavirus polymerase, protease or spike architecture can inform assay development and therapeutic design across related coronaviruses, while pan-orthomyxovirus surveillance must prioritise HA receptor specificity, NA balance, PB2 adaptation, mammalian replication markers and reassortment risk. Similarly, filovirus management benefits from comparing GP-mediated entry, VP35/VP24 immune antagonism and monoclonal antibody targets across ebolaviruses and marburgviruses (41, 42).

A central conclusion is that emergence cannot be inferred from sequence alone. Receptor usage, intracellular compatibility, restriction-factor sensitivity, environmental exposure and transmission opportunity form partly independent gates. Table 1 therefore the comparative synthesis of why selected viral families warrant different levels and types of preparedness; the ratings are qualitative decision aids, not forecasts (3, 43).

Table 1. Comparative synthesis of family-level emergence features, molecular gates, uncertainties and preparedness priorities.

3.2 Entry receptors, protease activation and tissue tropism

Entry is the first molecular gate through which an emerging virus must pass. Enveloped viruses use surface glycoproteins to bind receptors or attachment factors and then undergo fusion at the plasma membrane or within endosomal compartments. For SARS-CoV-2, ACE2 engagement and TMPRSS2-mediated spike priming provided a clear mechanistic explanation for cellular entry, while furin pre-activation broadened the range of permissive routes (9, 14, 15). For henipaviruses, ephrin-B2/B3 receptor usage helps explain endothelial and neuronal tropism; for filoviruses, macropinocytosis, glycoprotein processing and NPC1-dependent endosomal entry are central determinants of permissiveness.

Tropism is also determined by host proteases, attachment factors, glycan presentation and innate-state context. A receptor may be expressed in a tissue yet fail to support efficient infection if the proteolytic environment or replication cofactors are absent. Conversely, viruses can exploit multiple entry routes or evolve altered receptor-binding surfaces that expand their host range. This explains why entry studies should be integrated with organoid models, primary cells, pseudovirus assays and animal-interface surveillance, rather than being interpreted from receptor-binding data alone (Table 2) (10, 11, 43).

Table 2. Synthesis of conserved viral processes, vulnerabilities, evidence conflicts and validation requirements.

For vector-borne viruses, alternating replication in arthropod and vertebrate hosts creates both constraints and opportunities. Envelope adaptation can change vector competence or vertebrate tropism, but field emergence also depends on vector abundance, climate, immunity and mobility. Thus, molecular observations should be interpreted through the evidence ladder in Figure 2: computational or structural predictions generate hypotheses, whereas confidence increases only when primary-cell, animal and epidemiological evidence converges (5, 28, 43).

3.3 Replication complexes, genome architecture and assembly

Replication machinery is a second determinant of emergence. RNA-dependent RNA polymerases, viral proteases, nucleocapsid proteins and replication organelles determine not only viral yield but also mutation rate, recombination potential and sensitivity to nucleoside analogues. Coronaviruses are unusual among RNA viruses because their replication complex includes proofreading activity, enabling large genomes while still permitting adaptive diversity. This balance of fidelity and flexibility is one reason SARS-CoV-2 could accumulate meaningful mutations without losing genome integrity (7, 44, 45).

Assembly mechanisms differ across viral families but often expose vulnerabilities. Coronavirus assembly occurs at ER-Golgi intermediate compartments through coordinated interactions among M, E, S and N proteins. Influenza assembly requires packaging of eight genome segments, creating opportunities for reassortment but also imposing strict compatibility constraints. Filovirus budding depends heavily on matrix protein VP40 and host ESCRT machinery, while orthopoxviruses encode complex cytoplasmic replication and virion-assembly systems. These family-specific mechanisms can be exploited by antivirals, neutralising antibodies and vaccine antigen design.

Host-factor screens and proteomics have expanded the field from single viral proteins to systems-level replication networks. A SARS-CoV-2 protein-interaction map identified host pathways that could be repurposing targets, while CRISPR screens revealed TMEM41B and other host factors as pan-coronavirus dependencies (10, 11). Multi-omics analyses further showed that homologous coronavirus proteins can induce different transcriptomic, proteomic and phosphoproteomic perturbations, reinforcing that related viruses may share architecture while diverging in pathogenic effect (12).

3.4 Immune evasion, persistence and pathogenesis

Innate immunity imposes one of the strongest barriers to emergence. Pattern-recognition receptors detect viral RNA, DNA or replication intermediates and activate interferon, inflammatory and intrinsic restriction programmes. Successful emerging viruses frequently encode proteins that mask pathogen-associated molecular patterns, block adaptor proteins, degrade signalling molecules, suppress STAT activation, remodel stress responses or antagonise antigen presentation. These mechanisms are not incidental virulence accessories; they are often prerequisites for efficient replication in a new host (46–48).

Convergent immune-evasion logic can be seen across unrelated viruses. Influenza A NS1 inhibits antiviral RNA sensing and interferon responses. Ebola virus VP35 suppresses RIG-I-like receptor signalling, while VP24 interferes with interferon-induced nuclear import. Coronaviruses deploy several antagonists, including nsp1-mediated host translation suppression and accessory proteins that disrupt interferon signalling. Henipavirus V, W and C proteins impair interferon production or response, while orthopoxviruses encode multiple soluble and intracellular immunomodulators (8, 42, 49, 50).

Pathogenesis results from both direct viral injury and dysregulated host response. Severe disease may reflect tropism for endothelial, respiratory, neurological or immune cells, but also excessive inflammation, vascular leakage, coagulopathy or immunopathology. Persistent or latent infections add further complexity. Cytomegalovirus, although not usually discussed as a newly emerging virus, remains instructive because its immune-evasion repertoire shows how durable viral persistence can be sustained through interference with TLR, cGAS-STING, NF-kB, TBK1-IRF3, apoptosis, autophagy and ER-stress pathways (47, 51).

3.5 Genomic diversity, recombination and antigenic escape

Evolutionary dynamics determine whether control measures remain effective. SARS-CoV-2 demonstrated that variants can accumulate spike mutations that alter transmissibility, antigenicity and neutralisation while maintaining receptor engagement (7, 19–21, 23). Omicron showed that immune escape can become a dominant population-level advantage in settings of widespread infection- or vaccine-derived immunity, yet escape must remain compatible with entry and replication fitness.

Influenza viruses exemplify the risk of segmented genomes. Reassortment between avian, swine and human viruses can generate new constellations of internal genes and surface antigens, while point mutations in HA, PB2 and other segments influence receptor preference and mammalian adaptation. Highly pathogenic H5N1 clade 2.3.4.4b has increased concern because infection in mammals creates additional opportunities for adaptation, even though sustained human-to-human transmission has not been established (25, 26).

Genomic surveillance should therefore evaluate variants as phenotypic hypotheses rather than as lists of mutations. A mutation in a receptor-binding domain, polymerase, protease, matrix protein or immune antagonist may be important only in a specific genomic background. Variant assessment requires integrating phylogenetics, structural modelling, neutralisation assays, receptor studies, growth kinetics and clinical epidemiology. This is precisely where systems virology can reduce both underreaction to dangerous signals and overinterpretation of harmless sequence noise.

3.6 Diagnostics, surveillance and omics-driven interpretation

Rapid diagnostics are central to containment, but performance is conditional. RT-qPCR is sensitive and scalable, yet primer mismatch, sampling time, specimen quality and infrastructure can reduce effectiveness. Programmable CRISPR assays can shorten redesign cycles, whereas metagenomic sequencing can detect divergent or unexpected agents; neither replaces prospective clinical validation, contamination control or external quality assurance (32–34, 36).

Metagenomic next-generation sequencing (mNGS) offers agnostic detection when the causative agent is unknown, divergent or coinfecting. Clinical validation studies have shown that automated mNGS can detect respiratory viral pathogens from upper-respiratory and bronchoalveolar samples within operationally meaningful timeframes, while comparative evaluations show that untargeted sequencing, targeted enrichment and amplicon methods each have different trade-offs in sensitivity, specificity, cost and turnaround (36, 52).

Outbreak genomics converts sequences into public-health information. Ebola, Zika, yellow fever, SARS-CoV-2 and mpox have shown that phylogenetics can reveal introductions, hidden transmission, superspreading, international dissemination and the timing of interventions (27, 29–31, 53, 54). The value of genomic data depends on representative sampling, metadata quality, rapid deposition, analytic capacity and equitable participation by affected regions (Figure 3).

3.7 Vaccines, therapeutics and precision countermeasures

The COVID-19 pandemic demonstrated both the power and fragility of platform countermeasures. mRNA, adenoviral-vector and protein-based vaccines can be developed quickly when antigen design, manufacturing capacity, clinical trial networks and regulatory pathways are prepared in advance (35, 55–59). However, antigenic evolution can reduce neutralisation, requiring booster strategies, updated antigens or broader immunogen design.

Direct-acting antivirals are most useful when they target conserved enzymatic functions, have acceptable safety profiles and can be delivered early in infection. Remdesivir targets viral RNA polymerase and showed clinical benefit in hospitalised COVID-19 patients in selected settings, while nirmatrelvir-ritonavir reduced progression risk among high-risk outpatients when given early (60, 61). Molnupiravir demonstrated more modest clinical utility and raises different resistance and mutagenesis considerations (62).

For filoviruses, the PALM trial established that monoclonal antibody therapies can improve outcomes for Ebola virus disease when delivered with supportive care, shifting the field from empiricism towards evidence-based outbreak therapeutics (41). For mpox, tecovirimat has been widely used because of orthopoxvirus rationale and animal-rule approval, but recent human trial evidence for clade I mpox did not demonstrate faster lesion resolution, highlighting the need for outbreak-embedded randomised trials rather than reliance on plausible mechanism alone (63).

Vaccine deployment for emerging viruses must be integrated with genomic surveillance and equity. Ebola vaccination strategies illustrate how stockpiles, ring vaccination and preventive vaccination may be selected according to outbreak risk and vaccine regimen characteristics (64, 65). RSV prevention is a useful adjacent example of how monoclonal antibodies and maternal vaccination can reduce severe disease, although implementation depends on timing, supply and population access (66, 67) (Table 3).

Table 3. Comparison of under-represented emerging pathogens and priority evidence needs.

3.8 Plant, animal and One Health interfaces

Plant and animal viruses are therefore not peripheral; they are part of the same emergence continuum. Begomoviruses, canine distemper virus, avian influenza, coronaviruses in mink, and arboviruses maintained in vertebrate-vector cycles demonstrate that food security, animal health and human health are connected through molecular and ecological mechanisms (26, 68–70).

Operational One Health surveillance requires more than parallel sampling. Human sentinel data, livestock and wildlife events, vectors, wastewater or environmental signals, sequences and contextual metadata must enter a shared decision process with defined triggers and responsible institutions (Figure 3). Practical barriers include intermittent financing, specimen transport, biosafety, sequencing access, interoperability, delayed benefit sharing and shortages of trained analysts. Low-resource settings therefore need tiered networks that combine local diagnostic capacity with referral sequencing, quality assurance and reciprocal data access (Table 4) (71–73).

Table 4. Validation matrix for molecular and computational technologies used in emerging-virus preparedness.

4 Discussion

The synthesis supports a conditional—not deterministic—view of molecular emergence. Entry compatibility, efficient replication, immune antagonism and exposure can raise concern, but their predictive value changes with viral background and host context. A receptor-binding result or AlphaFold model is therefore a starting hypothesis, whereas consistent primary-cell, animal and epidemiological evidence can justify operational action (3).

Mechanism-informed management also protects against simplistic interpretations. Receptor binding alone does not equal pandemic risk, and a mutation list does not equal phenotype. Conversely, absence of known human transmission does not guarantee safety if exposure is increasing and the virus already possesses several compatible molecular features. Risk assessment should therefore integrate sequence, structure, cell biology, immunology, ecological exposure and epidemiological context (3, 74).

The interval between molecular discovery and useful intervention remains too long for many priority viruses. High-resolution structures, host-factor screens and interactome maps can identify candidate targets, but those targets must pass pharmacological, safety, delivery and resistance barriers. The COVID-19 experience showed that when platform readiness, trial networks and regulatory agility already exist, countermeasures can move rapidly; for other viruses, especially in under-resourced outbreak regions, the same pathway is slower and less equitable (2, 35).

Therapeutic development should prioritise conserved viral enzymes, host-assisted pathways with acceptable safety margins, and antibody targets that are functionally constrained. Yet highly variable surface glycoproteins remain essential vaccine and neutralising-antibody targets, requiring broadening strategies such as mosaic antigens, conserved epitope focusing, multivalent immunogens and rapid update capacity. The most robust management systems will combine broad preparedness with pathogen-specific refinement.

The evidence base is structurally uneven. SARS-CoV-2 offers abundant structural, clinical and population data, while Lassa virus, Crimean-Congo haemorrhagic fever virus (CCHFV), hantaviruses and Rift Valley fever virus (RVFV) remain comparatively under-characterised. This asymmetry can make publication volume appear equivalent to biological importance. Lassa-virus diversity and immune evasion complicate vaccine generalisation; CCHFV combines tick ecology with incomplete correlates of protection; hantavirus pathogenesis centres on endothelial dysfunction despite limited specific therapy; and RVFV risk spans livestock, vectors and human disease (75–77).

Conflicting evidence commonly arises from model choice. Receptor overexpression can exaggerate permissiveness; pseudoviruses isolate entry while omitting replication and immune antagonism; organoids improve tissue relevance but incompletely reproduce systemic immunity; and animal models may not capture human transmission. Consequently, apparently discordant results should be mapped to the biological level actually tested rather than averaged into a single conclusion.

Future research should connect molecular phenotyping with real-time surveillance. First, prototype-pathogen panels should be established for priority viral families and linked to standardised assays for entry, replication, innate immune sensitivity, antigenic escape and antiviral susceptibility. Second, genomic surveillance should incorporate metadata, sampling-denominator information and rapid data sharing so that variants can be evaluated in epidemiological context. Third, diagnostics should be stress-tested against genetic diversity before outbreaks expand.

Artificial intelligence can accelerate protein-structure prediction, variant prioritisation, epitope screening and surveillance anomaly detection. Protein language models and AlphaFold-derived structures can reveal remote similarities and candidate functions, yet confidence scores do not establish biological activity, host range or clinical relevance. Training-data bias, poor representation of disordered or dynamic complexes, distribution shift and limited prospective validation require that AI outputs remain auditable hypotheses tested against experimental and epidemiological data (78–80).

The proposed sequence-to-decision standard is deliberately modular. A novel signal should pass through five stages: detection and metadata review; family and structural triage; functional testing of entry, replication and innate responses; explicit evidence grading; and a proportionate decision about surveillance, assay updating, countermeasure screening or clinical research. Table 5 defines the minimum information required at each stage and prevents mechanistic plausibility from being presented as validated prediction.

Table 5. Minimum sequence-to-decision information set.

Virus-family-specific research priorities; Coronaviridae; Coronaviruses should remain a central target for family-level preparedness because they combine broad animal reservoirs, recombination, receptor plasticity and clinically important replication enzymes. Future work should prioritise pan-sarbecovirus and pan-merbecovirus antigen design, conserved protease and polymerase inhibitors, and functional phenotyping of animal coronaviruses before human outbreaks occur. Genomic surveillance should not only report spike mutations but also evaluate changes in non-structural proteins that influence replication fidelity, interferon antagonism and drug susceptibility (3, 7, 44).

A major research need is the integration of structural and population-level data. Spike structures can explain receptor affinity and antibody escape, yet public-health risk depends on whether those changes translate into efficient growth, shedding and transmission. A robust coronavirus preparedness platform should therefore connect sequence alerts to pseudovirus entry assays, live-virus or replicon assays where legally and ethically appropriate, neutralisation panels, animal-interface metadata and clinical-severity signals.

Orthomyxoviridae: Influenza A viruses require continuous attention because reassortment can create antigenically novel strains faster than gradual mutation alone. H5N1 clade 2.3.4.4b has reinforced the importance of monitoring mammals exposed to avian viruses, not because mammalian infection automatically implies pandemic transmission, but because each mammalian replication event provides opportunities for polymerase adaptation, receptor-preference shifts and altered tissue tropism (25, 26).

Priority studies should connect animal surveillance with functional markers of mammalian adaptation, including HA binding specificity, PB2 substitutions, polymerase activity at mammalian airway temperatures, NA balance and innate immune antagonism. Universal influenza vaccine research should be paired with rapid manufacturing and regulatory strategies, because a broadly protective antigen is most valuable when deployable before a zoonotic strain becomes widely transmissible.

Filoviridae and Paramyxoviridae: Filoviruses and henipaviruses illustrate how severe disease can arise from a combination of efficient entry, endothelial or neurological tropism and strong innate immune antagonism. For Ebola virus disease, monoclonal antibodies changed clinical expectations, but Sudan virus and Marburg virus still expose gaps in cross-species and cross-virus protection. Research priorities include pan-filovirus antibodies, improved vaccines for non-Zaire ebolaviruses, rapid diagnostics, and integrated clinical-trial readiness in regions at risk (41, 42).

For henipaviruses, the principal translational challenge is the gap between recognised pandemic concern and limited licensed countermeasures. Nipah virus research should continue to examine ephrin receptor usage, immune evasion by V/W/C proteins, respiratory versus neurological pathogenesis, bat reservoir ecology, and interventions that can be deployed in rural outbreak settings where diagnostic infrastructure may be limited (50, 81).

Flaviviridae and Togaviridae: Vector-borne RNA viruses require a dual molecular-ecological framework. Viral envelope mutations may alter receptor usage, thermostability or vector competence, but emergence also depends on mosquito or tick distribution, urbanisation, climate anomalies, immunity in the human population and travel networks. The continued threat of flaviviruses is therefore not a single-virus problem; it is a systems problem in which ecological surveillance, vector control, vaccine safety and genomic epidemiology must interact (5, 30, 73).

Chikungunya virus shows how alphavirus emergence can produce major morbidity even when mortality is lower than for haemorrhagic fever viruses. Research priorities include durable vaccines, antivirals that reduce acute viraemia and chronic sequelae, and diagnostics that distinguish chikungunya from dengue, Zika and other febrile illnesses in co-circulating regions. As with flaviviruses, evidence must be interpreted in the context of vector ecology and climate-sensitive transmission (40).

Orthopoxviruses and DNA-virus preparedness: Mpox demonstrates that large DNA viruses can still change their epidemiological behaviour under new transmission networks. Although orthopoxviruses mutate more slowly than many RNA viruses, their larger genomes encode multiple immunomodulators and host-range factors. The research agenda should prioritise clade-specific pathogenesis, transmission-route biology, vaccine effectiveness across populations, antiviral resistance, and clinical trials capable of rapidly evaluating therapeutics during outbreaks (8, 63, 82).

The broader lesson is that preparedness should not be restricted to RNA viruses. DNA viruses with complex immune evasion systems may emerge through ecological change, waning population immunity, altered contact networks or gaps in vaccination. Molecular management must therefore remain flexible enough to include both rapidly mutating RNA viruses and DNA viruses whose pathogenic potential depends on genome-encoded immune modulation and host-range genes.

Plant and veterinary viruses as preparedness sentinels: Plant and veterinary viruses often provide early evidence of how environmental pressure, vector movement and host management shape viral evolution. Begomovirus resistance research using artificial miRNA illustrates the value of molecular management in crop protection, while canine distemper and avian influenza surveillance show how animal viruses can signal broader ecological or host-range shifts (26, 69, 70).

Future One Health systems should integrate plant pathology, veterinary diagnostics and human public health rather than treating them as separate disciplines. Food-security pathogens, livestock pathogens and wildlife pathogens can create cascading social and economic effects, and some animal viruses may become direct zoonotic threats. A shared molecular surveillance architecture would improve early detection and reduce duplication of effort.

Across virus families, three implementation priorities recur. The first is assay standardisation. Cross-cutting priorities for implementation: Variant phenotyping should not depend on isolated laboratories using incomparable methods; instead, neutralisation panels, entry assays, replication assays and immune-evasion readouts should be standardised enough to allow comparison across time and geography. Standardisation does not eliminate innovation, but it prevents decision makers from receiving contradictory signals that arise from technical differences rather than biological differences.

The second priority is the connection between molecular evidence and public-health thresholds. Surveillance systems should define in advance which signals trigger further investigation, assay redesign, countermeasure review or public communication. Examples include repeated detection of a high-risk virus in a new host, convergent mutations at receptor-binding sites, loss of diagnostic target conservation, reduced neutralisation against vaccine-induced sera or molecular markers of antiviral resistance. Predefined thresholds would make response faster and more transparent.

The third priority is sustainable capacity. Genomic sequencing, biobanking, bioinformatics, clinical trials and vaccine delivery cannot be improvised during every outbreak. Capacity must exist before a crisis, especially in regions where spillover and neglected outbreaks are most likely to occur. This is a scientific, ethical and strategic requirement: without local capacity, the global community receives delayed data, affected communities receive delayed benefits, and molecular discoveries fail to become timely management.

5 Conclusion

Priority research should now focus on: (i) prototype panels and standardised phenotype assays for neglected viral families; (ii) prospective validation of AI and structural predictions; (iii) conserved antiviral and antigen targets tested against within-family diversity; (iv) diagnostic stress-testing before outbreaks; (v) outbreak-ready adaptive trials; and (vi) sustained, locally governed One Health genomic networks. The practical policy implication is that surveillance funding should cover the full path from sampling and metadata to interpretation and action, not sequencing alone. Molecular systems analysis cannot predict emergence with certainty, but evidence-graded integration can shorten the interval between a credible signal and a proportionate response while reducing both false reassurance and unjustified alarm.

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Footnotes

Edited by: Sangita Sahni, Dr. Rajendra Prasad Central Agricultural University, India

Reviewed by: Anne M. Hahn, Peter Doherty Institute for Infection and Immunity, Australia

Abhishek Vijukumar, Indo-Soviet Friendship College of Pharmacy, India

Footnotes

ACE2, Angiotensin-converting enzyme 2; APOBEC3, Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3; CRISPR, Clustered regularly interspaced short palindromic repeats; EBOV, Ebola virus; ERGIC, Endoplasmic reticulum-Golgi intermediate compartment; ESCRT, Endosomal sorting complexes required for transport; GP, Glycoprotein; HA, Haemagglutinin; IFN, Interferon; IRF, Interferon regulatory factor; ISG, Interferon-stimulated gene; JAK-STAT, Janus kinase-signal transducer and activator of transcription; mNGS, Metagenomic next-generation sequencing; MPXV, Mpox virus; NA, Neuraminidase; NPC1, Niemann-Pick C1; PRR, Pattern-recognition receptor; RdRp, RNA-dependent RNA polymerase; RLR, RIG-I-like receptor; RT-qPCR, Reverse-transcription quantitative polymerase chain reaction; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; STING, Stimulator of interferon genes; TLR, Toll-like receptor; TMPRSS2, Transmembrane serine protease 2.