What does prior exposure or advanced age change about the course of infection?
Clinical immunology of COVID-19 was constrained by what cannot be done in people. Whether immune memory prevents reinfection, whether it prevents onward transmission, and whether memory raised against one spike covers a divergent one all require controlled rechallenge, cohousing and adoptive transfer. Similarly, morbidity rose sharply with age, but whether that reflects more virus or a different response could only be settled by holding the virus constant and varying the host. A third question arrived with the northern winter, namely whether an airway already carrying one respiratory virus is more or less hospitable to another.
The golden hamster reproduced much of COVID-19 biology without host or virus adaptation, but commercial immunological reagents for the species were scarce, which had confined the model to viral load, histology and transcription.
All three publications carry lab-led, with tenOever as senior or lead contact.
Horiuchi 2021 built the reagent base and then used it. A flow cytometry approach was assembled from cross-reactive antibodies raised against human and mouse targets, with CXCR3, CXCR5 and Bcl6 reported as newly usable in this species, together with peptide restimulation and biotinylated spike probes and a validated adoptive transfer procedure exploiting the animals' inbred status. Against influenza A virus at comparable peak titre, SARS-CoV-2 required about two additional days to drive comparable NF-kappa B-associated and chemokine expression, and was followed by an adaptive response exceeding the response to influenza. Antigen-specific CD4 T cells and spike-specific B cells persisted beyond 40 days. Homologous rechallenge at more than four months left no recoverable infectious virus, yet all eight cohoused naive animals became infected. Adoptive transfer of B cell-depleted lymphocytes from recovered animals lowered nasal wash titres in naive recipients and was followed by rapid appearance of spike-specific B cells. Rechallenge with the B.1.351 beta variant gave equal early titres but complete clearance by four days in previously exposed animals, whose serum neutralized that variant poorly in vitro.
Oishi 2022 in Cell Reports held the virus constant and varied age. Lung titres were higher in young animals at one and three days and comparable at five and seven, so the aged phenotype is not explained by greater replication. Uninfected older lungs already showed lower TGF-beta signalling, lower NF-kappa B signalling and lower proliferation signatures. After infection chemokine induction was diminished and delayed, and interferon-stimulated gene profiles, comparable through three days, fell away rapidly thereafter despite equivalent virus. Ki67 staining confirmed reduced proliferation. Older animals failed to expand T cells or Th1 cells, carried more FoxP3-positive regulatory and CD8 T cells, showed elevated IL-17 staining in both lymphocytes and epithelium, and recruited more CD11b-positive neutrophils. Spike-specific B cell numbers and anti-receptor-binding-domain IgG titres were unchanged, but germinal centre B cells were markedly reduced in lung, spleen and draining lymph node and serum neutralizing potency fell by more than sixty percent, which the authors read as a deficit in affinity maturation rather than in production. IL-17 induction correlated with age in human COVID-19 cadaver lung transcriptomes.
Oishi 2022 in the Journal of Virology addressed coinfection with all three timings that matter epidemiologically. Influenza reduced SARS-CoV-2 replication during simultaneous coinfection and hastened its clearance, did so when given three days earlier, and still did so when given seven or fourteen days earlier, at which point infectious influenza was gone and only twenty-five genes remained differentially expressed in lung although ISG15 and IRF7 remained elevated. SARS-CoV-2 never changed influenza titres in the animal, though it did suppress influenza in interferon-competent A549 cells and not in interferon-deficient Vero E6 cells. Weight and histology in coinfected animals tracked SARS-CoV-2 rather than coinfection as such.
The unifying move is to treat the host as the variable. Horiuchi 2021 varies prior exposure, Oishi 2022 in Cell Reports varies age, and Oishi 2022 in the Journal of Virology varies recent infection history, all in one model with the same transcriptional index genes. Two results dissociate things usually assumed to travel together. Protection of the host and interruption of spread came apart in Horiuchi 2021, and serum neutralization and in vivo protection gave different answers about the beta variant in the same animals, which bears directly on how reduced neutralization titres against variants should be read. In Oishi 2022 in Cell Reports, virus burden, antibody quantity and bulk immune cell recruitment were all unchanged with age while the duration and quality of the response were diminished, which is what makes the phenotype tractable.
The limits here are mostly reagent-driven and causal. Horiuchi 2021 could not identify B cell-specific or CD8 T cell-specific populations directly, so the adoptive transfers test a B cell-depleted population rather than a defined subset, and the transmission from animals in which no infectious particle was detected is explained as transmission below the limit of detection, a proposal rather than a measured quantity. The authors state that the homologous rechallenge protection cannot be attributed to memory rather than to residual antibody, which makes the beta variant result the stronger of the two. Immunity was generated by infection rather than vaccination, and one founder strain and one variant were tested. In Oishi 2022 in Cell Reports every mechanistic link is correlational, with no depletion, blockade, transfer or receptor knockout, so the causal role of regulatory T cells, TGF-beta, IL-17 or neutrophils in the pathology is proposed rather than shown, cohort sizes were three to five animals, the two age blocks have no intermediate ages, and the human data are a transcriptional correlation in post-mortem lung. In the coinfection study the mechanistic claim rests on an association between residual ISG15 and IRF7 and reduced early replication, with no interferon blockade or cell depletion and no way to separate residual interferon-stimulated gene expression from increased resident immune cells, and only male animals of one age were used where a divergent result from another group came from female hamsters.
The interpretive frame comes from the imbalanced host response, and the delayed NF-kappa B kinetics reported by Horiuchi 2021 are read against the requirement for NF-kappa B-driven transcription established by Nilsson-Payant 2021, which Oishi 2022 in Cell Reports also invokes to interpret the lower early titres in older animals. The hamster platform and the interferon framing come from interferon as intervention, and the residual interferon-stimulated state that suppresses a later challenge in the coinfection study is the same priming logic that Carrau 2023 demonstrates within a single infection. The use of influenza A virus as a calibrated comparator recurs across the area and connects this theme to the laboratory's influenza work elsewhere in the corpus.
Comparison of young and older golden hamsters infected with SARS-CoV-2 shows that age reduces the magnitude and duration of the innate response and of tissue repair, expands suppressor T cells and IL-17-driven neutrophil recruitment, and lowers germinal centre B cell frequency and neutralizing antibody potency without raising lung virus titres.
In golden hamsters, influenza A virus infection reduces SARS-CoV-2 replication during coinfection, after preinfection, and even one to two weeks after influenza has been cleared, while SARS-CoV-2 leaves influenza replication in vivo unchanged.
Longitudinal tracking of antigen-specific lymphocytes in golden hamsters shows that memory from the founder strain of SARS-CoV-2 clears a beta variant rechallenge and that transferred memory T cells alone lower viral load, yet protected animals still infected every cohoused naive partner.