Immune trade-offs, inflammation dynamics, and metabolic costs during Streptococcus infections and co-infections in aquaculture fish: a comprehensive literature synthesis
Introduction
Research question and scope
This review examines experimental and multi-omic evidence (2015–2026) concerning immune trade-offs, inflammatory dynamics, and energetic/metabolic costs associated with Streptococcus infections and Streptococcus-containing co-infections in fish models commonly used in aquaculture (notably Nile tilapia Oreochromis niloticus, farmed salmonids, and zebrafish as an experimental model). The core questions addressed are:
- What immunological mechanisms mediate resistance (pathogen clearance) versus tolerance (minimizing host damage) during Streptococcus infection in fish, and what is the role of canonical pro- and anti-inflammatory cytokines (IL‑1β, TNF‑α, IL‑10/TGF‑β) in these dynamics?
- How do mono-infections with Streptococcus compare experimentally to co-infections (bacterial + bacterial or viral + bacterial) in terms of immune activation, pathology, and mortality?
- What quantitative evidence exists for metabolic costs (oxygen consumption/respiration, hepatosomatic index, plasma glucose/lactate, growth/condition metrics) and for immune‑metabolic pathway regulation (AMPK, mTOR, Akt) during infection?
- What mitigation strategies (vaccines, probiotics, dietary management) reduce inflammatory costs and improve survival and production outcomes in aquaculture?
Scope and evidence sources
All claims in this synthesis are strictly grounded in the peer-reviewed articles, field outbreak investigations, and experimental reports located and cited below. The focus prioritized primary experimental studies and high-quality reviews from 2015–2026 (selected journals: Frontiers in Genetics, Fish & Shellfish Immunology, Developmental & Comparative Immunology, BMC Biology, PLoS ONE, MDPI/Animals, Aquaculture, Pathogens). Citation tokens refer to normalized URLs as required (see inline citations). Each empirical claim includes 1–2 supporting citations where available.
Summary of key findings (headline)
- Streptococcus challenge in tilapia and other teleosts provokes rapid innate inflammatory responses—early IL‑1β and TNF‑α induction within hours, followed by anti‑inflammatory signals (IL‑10/TGF‑β) within 24–72 h—reflecting a canonical pro-inflammatory-then-resolving sequence that controls tissue damage if regulated, or causes pathology if excessive.
- Coinfection scenarios (Streptococcus + Aeromonas, Vibrio, or viral TiLV/IHNV) generally produce stronger transcriptomic activation, higher inflammatory gene expression, and more severe pathology and mortality than single Streptococcus challenges—field outbreaks and experimental co-challenges document synergistic effects on mortality (examples: 42% vs 6.7% in a Gyrodactylus+S. iniae trial; 70% mortality in a TiLV + Aeromonas + S. agalactiae outbreak).
- Quantitative measurements of global host metabolic costs specifically during Streptococcus infections (e.g., whole-animal O2 consumption, plasma glucose/lactate, HSI) are surprisingly sparse; most direct metabolic-respirometry data come from immune‑challenge models (LPS, killed Vibrio) or viral challenges in salmonids. General patterns from experimentally immune‑stimulated fish show transient increases in resting metabolic rate (RMR) and/or maximal metabolic rate (MMR) and decreases in growth/body mass—indicating that metabolic trade-offs often manifest as reduced energy available for growth rather than absolute inability to raise ATP production.
- Molecular immune-metabolic signaling in tilapia implicates AMPK as a context-dependent regulator connecting fasting/energetic state to T‑cell autophagy and outcome after Aeromonas infection: short-term AMPK activation (2–3 days fasting) enhances adaptive cellular responses and survival, while prolonged activation triggers autophagy–apoptosis and worsens outcomes. Akt/mTORC1 signaling supports lymphocyte activation and proliferation in adaptive-stage responses. These axes provide mechanistic routes for energy-allocation trade-offs between immunity and growth/reproduction.
- Interventions (bivalent oral vaccines, probiotics) can significantly increase survival (RPS 77–82% reported for an oral bivalent S. iniae + A. hydrophila vaccine) and modulate cytokine profiles (heightened IL‑1β/TNF‑α early and TGF‑β/TGF‑β-like anti‑inflammatory responses later), but data linking interventions to reduced whole‑animal metabolic costs are limited. Probiotic feed additives frequently improve growth and feed efficiency and reduce pathogen load, indirectly mitigating energy trade-offs.
Section I — Descriptive overview of immune responses to Streptococcus infection in fish
- Time course and cytokine kinetics
Early pro-inflammatory phase (hours to ~24 h): Multiple experimental challenge studies report early and robust upregulation of proinflammatory cytokines such as IL‑1β and TNF‑α in teleost leukocytes/tissues following Streptococcus iniae or S. agalactiae exposure. In European seabass, IL‑1β and TNF‑α mRNA peaked between 4–8 h post-infection and declined by 48 h while anti‑inflammatory IL‑10 increased and peaked at 48 h, supporting a rapid-onset inflammatory response followed by regulatory signaling.
Intermediate adaptive/mucosal responses (1–7 days): Transcriptomic studies in Nile tilapia spleen and intestine during Streptococcus infection (and coinfection) show early chemokine/cytokine induction (e.g., CXCL10, CCL19, IL‑1β) and rising expression of immunoglobulin heavy chains (IgM, IgT) sustained to 7 days, indicating transition to adaptive or humoral defenses concurrent with innate inflammation. This pattern was stronger in coinfection experiments (S. agalactiae + S. iniae) where cytokine/chemokine pathways and antigen-presentation components were among the most enriched KEGG categories.
Late resolution or chronic inflammation: Anti‑inflammatory cytokines (IL‑10 or TGF‑β) and regulatory pathways become evident by 48–96 h in several vaccine and infection studies; effective resolution correlates with reduced tissue damage, whereas failure to regulate early inflammation is associated with organ pathology (e.g., liver congestion, splenic melanomacrophage activation) and mortality. Oral vaccination studies report both early pro-inflammatory responses and later TGF‑β upregulation (e.g., TGF‑β up to 8–9-fold in vaccinated spleen), which likely supports mucosal tolerance and tissue repair post-challenge.
- Cellular effectors and innate mechanisms
Phagocytes and respiratory burst: Streptococcus infection is associated with neutrophil and macrophage recruitment (chemokines CXCL10/CCL19), enhanced expression of complement and antigen-processing genes, and activation of proteasome/immunoproteasome components for antigen presentation. Some Streptococcus strains actively suppress phagocyte respiratory burst and peroxidase content, impairing intracellular killing—mechanistically linking virulence with immunopathology.
Humoral immunity: IgM and mucosal IgT responses in intestine and systemic tissues rise over days post-infection; vaccine studies document higher IgM titers and enhanced protection (RPS) correlating with upregulated Ig gene expression.
- Transcriptomic signatures and pathway enrichment
- Commonly enriched host pathways after Streptococcus challenge include cytokine-cytokine receptor interaction, TLR and NOD-like receptor signaling, proteasome/immunoproteasome for antigen processing, phagosome, and oxidative phosphorylation (often downregulated in severe/virulent strains). Multi-omic comparisons between virulent (HN016) and attenuated (YM001) S. agalactiae strains show virulence-associated suppression of oxidative phosphorylation and upregulation of inflammatory/NLR pathways in host spleen/liver, linking immune activation with metabolic reprogramming.
Boxed example: Tilapia intestine coinfection RNA-seq (Cui et al., 2022): coinfected intestine showed 6,185 DEGs (3,876 up, 2,309 down) and stronger upregulation of chemokines, IL‑1β, immunoproteasome subunits (PSMB8 >250-fold in coinfected intestine) compared to single infections—peaking at 24 h post-infection.
Section II — Comparative analysis: mono-infection vs. coinfection outcomes
- Mortality and pathology: evidence for synergy
- Observational outbreak data and experimental co-challenge studies converge on a pattern: co-infections involving Streptococcus plus bacterial (Aeromonas, Vibrio) or viral (TiLV, aquatic birnaviruses) agents typically produce higher mortality and more severe organ pathology than single-agent infections. Examples include natural outbreaks of TiLV + A. hydrophila + S. agalactiae with ~70% mortality and experimental co-challenges (Gyrodactylus + S. iniae) producing 42.2% mortality vs 6.7% for S. iniae alone in some trials. Case series emphasize the role of primary agents (virus or parasite) as “gateways” that increase bacterial proliferation and systemic invasion.
Refer to visual summary (examples compiled from extracted reports):
(Figure caption: illustrative examples extracted from outbreak and experimental reports showing higher mortality in co-infections; individual study details cited in text.)
- Molecular and transcriptomic amplifications during co-infection
- Coinfection tends to amplify cytokine and chemokine transcription, immunoproteasome components, and antigen‑presentation machinery relative to single infections. Cui et al. (2022) reported stronger early (≤24 h) chemokine and IL‑1β expression and larger DEG sets in coinfected tilapia intestine than in single-agent groups. Dual-omics studies in spleen/liver show virulent strains or coinfected contexts downregulate oxidative phosphorylation while upregulating inflammatory/NLR and TNF pathways—consistent with inflammatory-driven metabolic reprogramming and possibly impaired cellular energy supply in affected organs.
- Functional consequences for host physiology
- Field pathology commonly shows multi-organ damage in co-infections (brain meningitis, hepatic necrosis, renal tubular degeneration, splenic activation of melanomacrophage centers) and higher systemic bacterial burdens, which is consistent with greater inflammatory tissue damage and impaired organ metabolic function in coinfected fish. These outcomes suggest coinfections shift the host balance towards damaging inflammatory responses and overwhelmed clearance pathways.
Section III — Quantifying metabolic costs: available metrics and gaps
This section synthesizes the available quantitative evidence and highlights measurement gaps for common metrics requested by the user (oxygen consumption / respirometry, hepatosomatic index, plasma glucose/lactate, and transcriptomic/proteomic signatures of AMPK/mTOR/Akt pathways).
- Oxygen consumption and whole-animal respiration
Direct respirometry during Streptococcus infection: The literature search found no published respirometry studies that measured whole-animal oxygen consumption (MO₂, RMR or MMR) during live Streptococcus infections in tilapia, salmonids, or zebrafish. Instead, several relevant references used immune proxies or other pathogens: LPS or heat‑killed Vibrio challenges in zebrafish show temperature-dependent RMR increases (e.g., 30% increase at 27.5°C following heat‑killed Vibrio), and experimental viral infection studies in sockeye salmon (IHNV/PRV) measured SMR changes (IHNV: 19% reduction in SMR associated with resistance while PRV tolerance caused minimal respiratory effects). These findings imply that whole-animal respiration can change with immune activation, but direct Streptococcus-respirometry data are lacking and thus cannot be used to quantify Streptococcus-specific respiratory costs.
Viral comparison (mechanistic insight): The sockeye salmon study (IHNV vs PRV) provides a useful comparator: resistance to a virulent virus involved a statistically significant 19% decrease in SMR in early phases, whereas tolerance to a persistent virus showed minimal energetic burden despite high viral loads. Mechanistically, this indicates that resistance responses and their associated tissue damage can alter basal respiration, but that the energy cost is pathogen- and pathway-specific.
- Hepatosomatic index (HSI), body/condition metrics, and growth
- HSI and growth during Streptococcus infection: Several pathogenesis and vaccine trials report gross organ changes (hepatomegaly, splenomegaly) and body weight outcomes post-vaccination or infection. However, measured HSI values during Streptococcus infection are inconsistently reported; experimental diet and vaccine trials often report HSI unaffected by dietary inositol or vaccination but do not quantify HSI during acute Streptococcus infection. Growth impairments or reduced weight gain have been observed in immune-challenge experiments using LPS or antigenic stimulation (e.g., mosquitofish LPS-challenge lost ~4% body mass in 7 days), suggesting reduced assimilation or increased maintenance costs as likely trade-off manifestations. Tilapia Streptococcus studies often report anorexia and reduced feed intake during outbreaks, but precise population-level HSI datasets remain scarce.
- Plasma glucose and lactate
- Plasma glucose/lactate during Streptococcus infection: The systematic search did not retrieve primary reports that quantified plasma glucose or lactate specifically during Streptococcus infections in tilapia or zebrafish within 2015–2026. Some multi-omic or metabolomics adjunct studies indicate shifts in carbohydrate-related metabolites under thermal stress or bacterial virulence contexts (e.g., increased carbohydrate abundance at higher temperatures correlating with higher mortality in S. agalactiae outbreaks), but explicit plasma glucose/lactate time-series during Streptococcus infection and their relation to immune cytokine dynamics remain unreported. One E. tarda infection reference cited decreased glucose in tilapia, but it did not concern Streptococcus. Thus, a major empirical gap exists for metabolic blood markers during streptococcal disease.
- Oxidative stress and antioxidant enzyme measures
- Several Streptococcus pathogenesis studies measured oxidative stress markers in liver and kidney (NO, GSH, GPx, SOD, CAT, MDA) during infection, showing increased NO and MDA and decreased antioxidant enzyme activities at days 3 and 7 post-infection—consistent with inflammation-induced oxidative damage in organs. These biochemical changes indicate elevated local metabolic stress and ROS burden during infection but are organ-level markers rather than whole-organism energy budgets.
- Transcriptomic/proteomic evidence linking immune and metabolic pathways (AMPK, mTOR, Akt)
AMPK: A recent integrative study in tilapia demonstrates that AMPK activation is a key mediator linking energetic status to T cell function and outcome after Aeromonas infection. Short-term fasting (2–3 days) activated AMPK, increased autophagy markers, and improved T cell activation/proliferation and survival after bacterial challenge; long-term fasting (>7 days) led to excessive autophagy and apoptosis, reducing adaptive immunity. These effects were functionally validated with pharmacological modulators (Compound C/Metformin) and autophagy inhibitors (3‑MA), connecting metabolic sensing to immune trade-offs. This provides a mechanistic example of how energetic state manipulates immune allocation.
Akt/mTORC1: Akt1 and mTORC1 signaling support lymphocyte activation and proliferation in the adaptive immune phase in tilapia challenged with Aeromonas; inhibition of Akt1 reduced mTORC1 activation and impaired T cell activation/proliferation. Thus, mTORC1 acts as a pro-growth, pro-proliferation signal for adaptive responses, while AMPK signals favoring autophagy can, depending on intensity and timing, support or impair adaptive responses—illustrating opposing energy-sensing mechanisms that shape immune trade-offs.
- Quantitative meta-analysis: feasibility and constraints
- The dataset assembled during this review reveals abundant transcriptomic and qualitative mortality data but limited standardized quantitative metabolic measures for Streptococcus infections (MO₂, plasma glucose/lactate, HSI). Because of variable experimental designs (different challenge routes, doses, fish ages/sizes, environmental conditions), heterogeneous endpoints, and the sparse respirometry or plasma metabolite data for Streptococcus specifically, a statistically robust meta-analysis quantifying a pooled metabolic cost of Streptococcus infection (e.g., percent increase in RMR or oxygen consumption) is not feasible at present. Instead, the review presents targeted quantitative exemplars from related immune-challenge studies (LPS, viral infections) and compiled transcriptomic DEG magnitudes as surrogate indicators of host response intensity. For transparency, transcriptomic DEG counts for two large host studies are shown below as a proxy for response amplitude:
(Figure caption: two examples—intestine coinfection RNA-seq reported 6,185 DEGs (Cui et al., 2022), spleen dual-omics HN016 vs control reported 12,338 DEGs—these illustrate the scale of transcriptional remodeling.)
Section IV — Evolutionary interpretation: resistance vs tolerance trade-offs
- Theoretical framing
- Resistance is the host strategy that reduces pathogen burden (clearance); tolerance reduces harm without necessarily decreasing pathogen load. Evolutionary theory predicts both strategies can involve costs: resistance may require resource allocation to immune effectors and collateral tissue damage; tolerance may require reconfiguration of physiology to withstand infection while allowing pathogen persistence. The fish literature provides empirical cases consistent with both strategies, but costs are context dependent.
- Empirical patterns and interpretation
Short-term high inflammation and resistance: Several experimental systems indicate robust early inflammatory responses (IL‑1β/TNF‑α induction) are associated with pathogen clearance and short-term survival benefits. In tilapia, stronger immune gene expression after coinfection or virulent strains sometimes correlated with reduced mortality when containment was successful. However, high inflammation can also cause tissue damage and physiologic impairment: pathogenesis studies document respiratory burst suppression by pathogens, ROS accumulation, and oxidative damage to liver and kidney—hearteningly, when anti‑inflammatory signals (IL‑10/TGF‑β) and adaptive responses (IgM) follow appropriately, tissue damage is limited.
Tolerance as an energetically efficient route: The BMC Biology study in sockeye salmon (IHNV versus PRV) found that tolerance to a persistent virus produced minimal long-term respiratory cost, whereas resistance to a virulent virus involved measurable alteration in SMR (19% reduction early), suggesting that tolerance may be energetically efficient but allows pathogen persistence. Applied to Streptococcus, a tolerance strategy (e.g., limiting inflammation while maintaining tissue function) could be beneficial in certain aquaculture contexts where pathogen eradication is unlikely or where tissue damage would reduce production value; however, tolerance may maintain pathogen reservoirs and transmission risk.
Net fitness consequences and life-history trade-offs: Evidence from immune-challenge experiments (LPS) indicates that immune activation can reduce growth or body mass in the short-term (e.g., ~4% mass loss over 7 days in mosquitofish), implying a direct allocation cost potentially affecting reproduction and long-term fitness under chronic or repeated infection exposure. While explicit measures of reproductive output after Streptococcus infection are rare in aquaculture literature, the combination of anorexia, reduced growth, organ pathology, and oxidative stress indicates plausible reductions in long-term fitness if outbreaks are recurrent or prolonged.
- Synthesis: can heightened inflammation confer short-term survival at long-term cost?
- Yes, with caveats: Short-term heightened inflammation and resistance can increase immediate survival in many Streptococcus challenge contexts, but if inflammation is excessive, poorly regulated, or prolonged (as observed in some virulent strain infections and in long-term fasting/AMPK-activated contexts), the result is organ damage, reduced metabolic capacity, and impaired growth—components of long-term fitness cost. Conversely, controlled inflammation followed by regulatory responses (IL‑10/TGF‑β) and effective humoral immunity (IgM/IgT) tends to improve survival without large energetic penalties. The net evolutionary trade-off likely depends on pathogen virulence, environmental stressors (temperature, DO), and host energetic state.
Section V — Management implications for aquaculture (vaccines, probiotics, diets, and husbandry)
- Vaccination strategies and immune modulation
Oral/immersion and injectable vaccines against Streptococcus spp. in tilapia are widely studied: feed-based bivalent vaccines (S. iniae + A. hydrophila) have produced strong mucosal and systemic immune responses (early IL‑1β/TNF‑α, later TGF‑β expression) and high RPS (≈77–82% against the targeted pathogens). Vaccination is effective at boosting specific antibodies and reducing mortality but has not been widely tested for its effects on whole-animal metabolic costs. Integration with good husbandry and temperature control is recommended.
Live attenuated and subunit vaccines (e.g., attenuated S02 strain, YM001 strains) show promise with high RPS and apparent modulation of host carbohydrate metabolism pathways in bacterial strains, but their influence on fish energy allocation during infection has not been quantified in respirometric terms.
- Probiotics and dietary interventions
- Probiotics (Lactobacillus plantarum, Bacillus spp.) and feed-based functional supplements consistently improve growth performance and resistance to Streptococcus (reduced pathogen load, improved gut microbiota, higher lysozyme expression); these effects likely reduce energy reallocation costs by maintaining better nutritional status and mitigating inflammation-driven anorexia. For example, L. plantarum supplementation improved feed efficiency and increased thrombocytes/neutrophils post-challenge. Several studies report improved growth and reduced disease susceptibility with Bacillus-based probiotics. However, explicit links demonstrating reduced oxygen consumption or plasma metabolite stabilization after probiotic administration in Streptococcus infections are lacking.
- Husbandry and environmental control
- Environmental stressors (elevated temperature, low dissolved oxygen) exacerbate Streptococcus outbreaks (higher pathogen growth and host susceptibility) and are important modulators of immune-metabolic trade-offs. Temperature effects include increased pathogen metabolic activity and altered host intestinal morphology, while hypoxia reduces phagocytic ROS and antibody titers and increases mortality after challenge. Practical management should prioritize DO, temperature control, stocking density, and feed quality to minimize energetic constraints on immunity.
- Antimicrobial stewardship
- Antibiotic use is common but undermined by rising antimicrobial resistance in Streptococcus isolates; alternatives (vaccination, probiotics, herbal extracts, bacteriophages) are recommended within integrated disease management plans to lower long-term energetic and economic costs of outbreaks while avoiding AMR-mediated health threats.
Section VI — Synthesis framework and recommended research agenda (gaps and future directions)
A proposed integrative framework for future research and aquaculture translation
- Descriptive axis (innate/adaptive dynamics)
- Standardize time-series sampling (0h, 6h, 12h, 24h, 48h, 7d, 14d) across tissues (gill, intestine, spleen, kidney, liver) in controlled Streptococcus infection and coinfection models to map cytokine kinetics (IL‑1β, TNF‑α, IL‑6, IL‑10/TGF‑β), immune cell recruitment, and histopathology. Include both single-strain virulent and attenuated strains for direct virulence comparisons. Use qPCR, ELISA where available, and histology for tissue damage scoring. (Rationale: current datasets show early IL‑1β/TNF‑α peaks and later regulatory cytokines but lack harmonized cross-study timelines for direct synthesis.)
- Comparative axis (mono- vs co-infection)
- Perform controlled factorial co-challenge experiments (e.g., S. agalactiae or S. iniae alone vs. S. + Aeromonas vs. S. + TiLV) with matched pathogen doses and fish physiological states; measure survival curves, organ bacterial/viral load, cytokine profiles, and organ histopathology. (Rationale: field studies and sporadic experiments show synergistic mortality but lack mechanistic time-resolved data.)
- Quantitative metabolic axis (respirometry, HSI, plasma metabolites)
- Integrate whole-animal respirometry (intermittent-flow or closed-chamber MO₂ measurements for RMR and MMR) with simultaneous sampling of plasma glucose, lactate, cortisol, and HSI/body condition across infection timepoints. Apply these measures to single and coinfection experiments, and to vaccinated/probiotic-treated cohorts. (Rationale: direct MO₂ and plasma metabolite data are scarce for Streptococcus and are critical to quantify energetic trade-offs.)
- Mechanistic multi-omics axis (AMPK/mTOR/Akt, metabolomics)
- Combine transcriptomics (RNA‑seq), targeted phospho-proteomics (p‑AMPKα Thr172, p‑Akt1, p‑S6), and targeted metabolomics (glycolytic and TCA intermediates, ATP/ADP ratios) in the same individuals to directly connect immune signaling with energetic flux. Use pharmacological perturbations (AMPK activator/inhibitor, mTOR inhibitors) to causally test hypotheses about metabolic sensing shaping immune allocation. (Rationale: AMPK/Akt/mTOR are implicated experimentally in tilapia/Aeromonas contexts; broader multi-omics integration during Streptococcus infection would elucidate cross-talk.)
- Environmental modulation and climate interactions
- Explicitly test temperature and hypoxia interactions with infection and metabolic costs (e.g., factorial design crossing temperature × DO × infection) because temperature strongly modulates pathogen virulence and host metabolic budget. (Rationale: high temperature can accelerate bacterial virulence and shift host energy allocation; DO modulates phagocytic ROS and antibody titers.)
- Applied translation testing
- Trials in commercial-scale cohorts testing vaccine/probiotic/dietary strategies with integrated metabolic and immune endpoints will provide evidence for interventions that minimize immune-metabolic trade-offs while maintaining production metrics (growth, FCR, survival). Include economic cost–benefit analysis linking reduced mortality/growth losses to intervention costs. (Rationale: many studies show immune enhancement or improved growth with interventions, but few quantify how these alter energy budgets or production economics.)
Section VII — Tables and structured comparisons
Table 1. Representative experimental and field studies on Streptococcus single vs. co-infections (selected primary sources)
| Study (short ref) | Species | Pathogen(s) & type | Experimental design / outbreak context | Key immune/metabolic measures | Key outcome |
|---|---|---|---|---|---|
| Cui et al., 2022 (Frontiers Genet) | Nile tilapia | S. agalactiae + S. iniae (coinfection) | IP injection, single vs coinfection; intestine RNA-seq 6–24 h, 7 d | RNA-seq DEGs, RT-qPCR cytokines (IL‑1β), proteasome | Coinfection produced stronger early inflammatory and antigen-presentation responses; 6,185 DEGs reported; IL‑1β peaked ≤24 h. |
| Zhou et al., 2020 (FSI) | Nile tilapia | S. agalactiae (HN016 virulent, YM001 attenuated) | Infection study; liver/intestine proteome + transcriptome | Dual RNA-seq/TMT proteomics; oxidative phosphorylation, NLR/TLR pathways | HN016 induced stronger inflammatory/NLR signaling and downregulated oxidative phosphorylation vs YM001. |
| MDPI Animals (2020, outbreak) | Red hybrid tilapia | TiLV + A. hydrophila + S. agalactiae | Field outbreak natural triple infection; PCR, histopathology | Histopathology, pathogen detection, mortality | Triple co-infection associated with 70% mortality and severe organ lesion patterns. |
| Polinski et al., 2021 (BMC Biol) | Sockeye salmon | IHNV (virulent) and PRV (persistent) | Controlled viral infections, full respiratory physiology | Respirometry (SMR, MMR), hematology, ISG transcription | Resistance to IHNV linked to 19% SMR reduction; PRV tolerance produced minimal respiratory cost—innate antiviral defense energetically efficient. |
| Bonneaud et al., 2016 (PLoS ONE) | Mosquitofish (immune model) | LPS (immune stimulant) | IP injection; respirometry RMR/MMR, mass change | RMR, MMR, metabolic scope, mass change | LPS increased RMR and MMR transiently and reduced body mass (≈4% loss at 7 d). Shows immune activation redirects energy away from growth. |
Table 2. Typical cytokine timing and functional role inferred from experimental studies
| Cytokine | Timing after Streptococcus challenge | Main role and experimental observations |
|---|---|---|
| IL‑1β | Early (4–24 h peak) | Pro-inflammatory; neutrophil/macrophage activation; high in coinfection and virulent strains; declines by 48–72 h if controlled. |
| TNF‑α | Early (4–24 h) | Cooperates with IL‑1β in inflammation; elevated in vaccinated and infected tissues; linked to pathology when sustained. |
| IL‑10 / TGF‑β | Later (24–72 h peak) | Anti‑inflammatory/regulatory; upregulated in vaccine-protection contexts and during resolution to limit tissue damage. |
Conclusion
Synthesis of evidence
Streptococcal disease in aquaculture fish elicits rapid innate inflammatory responses (IL‑1β, TNF‑α) followed by adaptive humoral responses and anti‑inflammatory regulatory signals; coinfections amplify transcriptional and inflammatory intensity resulting in worse pathology and higher mortality. Multilayer omics (transcriptome/proteome) consistently indicate upregulation of NLR/TLR/cytokine networks and, in severe infections, suppression of oxidative phosphorylation in host tissues—implying tissue-level metabolic compromise.
Quantitative whole-animal metabolic data for Streptococcus infections are currently insufficient to estimate a generalizable percent increase in RMR or oxygen consumption specific to streptococcosis. Related immune-challenge and viral infection studies demonstrate that immune activation can increase RMR, transiently increase MMR and metabolic scope, and reduce growth/body mass—indicating that energetic trade-offs more consistently manifest as reduced growth or reproduction rather than absolute inability to raise ATP output.
Mechanistically, AMPK and mTOR/Akt pathways are central regulators of immune-metabolic trade-offs in teleosts: AMPK activation under short-term energetic stress can promote autophagy and improve adaptive T cell responses, but prolonged activation is detrimental; mTORC1/Akt1 promotes lymphocyte proliferation and adaptive responses. These two axes provide actionable targets for intervention studies aiming to optimize resistance while limiting metabolic costs.
Practical implications
- Integrated disease management that lowers pathogen exposure and environmental stress (temperature/DO), combined with vaccination and probiotic/dietary strategies, is currently the most evidence-based route to reduce the energetic and production costs of streptococcosis. However, quantitative demonstrations showing that these interventions reduce organismal metabolic costs during infection (measured as MO₂, normalized RMR/MMR, plasma glucose/lactate, or HSI) remain limited and represent a priority research need for translational aquaculture.
Limitations
Evidence base limitations: The literature search found rich transcriptomic/proteomic datasets and many challenge or outbreak reports but relatively few studies that measured whole-animal respiration (MO₂), plasma glucose/lactate, or robust HSI time-series specifically during Streptococcus infection. Therefore, quantitative claims about metabolic costs during streptococcal disease are necessarily conservative and rely on analogs (LPS/viral challenge) for mechanistic extrapolation. All claims are constrained to the cited studies above.
Heterogeneity of experimental designs: Variation in species, pathogen strains, challenge dose/routes, fish age/size, environmental conditions (temperature, DO), and endpoints reduced comparability and prevented meta-analytic pooling of metabolic effect sizes for streptococcal infections.
TLDR (key takeaways)
- Streptococcus infections provoke canonical pro-inflammatory responses (IL‑1β/TNF‑α) early, followed by adaptive activation and regulatory cytokines; coinfections intensify inflammation and mortality.
- Quantitative whole-animal metabolic data during Streptococcus infections are scarce; analogous immune-challenge and viral studies show immune activation often reduces growth and can alter basal metabolism, but results are pathogen- and context-specific.
- AMPK and Akt/mTORC1 are central immune–metabolic regulators: AMPK activation (fasting) can improve or harm adaptive immunity depending on duration/intensity; Akt/mTORC1 supports lymphocyte activation/proliferation. These pathways are promising targets for interventions.
- Vaccines and probiotics reduce mortality and pathogen loads and modulate cytokine responses; future work must quantify whether such interventions reduce host metabolic costs during infection.
Selected primary sources (representative list for further reading)
Cui M, Wang Z, Yang Y, Liu R, Wu M, Li Y, Zhang Q, Xu D (2022). Comparative Transcriptomic Analysis Reveals the Regulated Expression Profiles in Oreochromis niloticus in Response to Coinfection of Streptococcus agalactiae and Streptococcus iniae. Front. Genet. 13:782957. https://www.frontiersin.org/articles/10.3389/fgene.2022.782957/full
Zhou Y, Liu Y, Luo Y, Zhong H, Huang T, Liang W, Xiao J, Wu W, Li L, Chen M (2020). Large-scale profiling of the proteome and dual transcriptome in Nile tilapia (Oreochromis niloticus) challenged with low- and high-virulence strains of Streptococcus agalactiae. Fish & Shellfish Immunology, 100:386–396. https://doi.org/10.1016/j.fsi.2020.03.008
Polinski MP, Zhang Y, Morrison PR, Marty GD, Brauner CJ, Farrell AP, Garver KA (2021). Innate antiviral defense demonstrates high energetic efficiency in a bony fish. BMC Biology 19:138. https://doi.org/10.1186/s12915-021-01069-2
Bonneaud C, Wilson RS, Seebacher F (2016). Immune-Challenged Fish Up-Regulate Their Metabolic Scope to Support Locomotion. PLoS ONE 11(11): e0166028. https://doi.org/10.1371/journal.pone.0166028
Li K, Wei X, Li K, Zhang Q, Zhang J, Wang D, Yang J (2023). Dietary restriction to optimize T cell immunity is an ancient survival strategy conserved in vertebrate evolution. Cell Mol Life Sci. 80:219. (Summary/PMCID available)
Ai K, Yan J, Li K, et al. (2021). Akt1/mTORC1 signaling modulates adaptive immune response of Nile tilapia by promoting lymphocyte activation and proliferation. Developmental & Comparative Immunology 119:104042. https://doi.org/10.1016/j.dci.2021.104042
Vakil K et al., (2020). Co-infections of Tilapia Lake Virus, Aeromonas hydrophila and Streptococcus agalactiae in Farmed Red Hybrid Tilapia (Animals). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698767/
Abdallah ESH, Metwally WGM, Abdel-Rahman MAM, Albano M, Mahmoud MM (2024). Streptococcus agalactiae Infection in Nile Tilapia (Oreochromis niloticus): A Review. Biology 13(11):914. https://doi.org/10.3390/biology13110914
Selected intervention studies: Feed-based bivalent vaccine (red tilapia) demonstrating RPS ≈ 77–82% with cytokine modulation
and probiotic supplementation improving growth and resistance
If you would like, I can:
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