Within the substantially different time scales characterizing human and rodent brain development, key developmental processes are remarkably preserved. Shared processes include neurogenesis, ...myelination, synaptogenesis, and neuronal and synaptic pruning. In general, altricial rodents experience greater central nervous system (CNS) immaturity at birth and accelerated postnatal development compared to humans, in which protracted development of certain processes such as neocortical myelination and synaptic maturation extend into adulthood. Within this generalization, differences in developmental rates of various structures must be understood to accurately model human neurodevelopmental toxicity in rodents. Examples include greater postnatal neurogenesis in rodents, particularly within the dentate gyrus of rats, ongoing generation of neurons in the rodent olfactory bulb, differing time lines of neurotransmitter maturation, and differing time lines of cerebellar development. Comparisons are made to the precocial guinea pig and the long-lived naked mole rat, which, like primates, experiences more advanced CNS development at birth, with more protracted postnatal development. Methods to study various developmental processes are summarized using examples of comparative postnatal injury in humans and rodents.
Spontaneous animal models of Alzheimer’s disease (AD) offer the potential to bridge the translational gulf between promising rodent studies and failed human clinical trials. In this review, the ...relationship between cell biology, neuropathology, clinical phenotype and biomarker progression in human AD is summarized. Genetically altered animals have provided key insights into the cell biology of AD and, together with emerging stem cell systems, remain the most effective means to disentangle the entwined mechanisms that underlie AD. Translating therapeutic success from these models of familial AD to late onset human AD has been challenging. Spontaneous models of AD do not harbor AD-associated mutations and could potentially be used to demonstrate greater generalizability of new therapies to late onset AD. The value of such models has been advanced primarily on the basis of similar amyloid (and far less frequent, tangle) neuropathology. While these models are promising, this alone is insufficient for use of these models to assess efficacy of potential therapies. The correlation between progression of neuropathology and cognitive phenotype and the association of these with biomarker progression in these models is discussed, with an emphasis on the dog and non-human primates. Currently, interventional studies using these models are hampered by use of a variety of outcomes that are not easily comparable with those used in human trials and do not permit longitudinal assessment. Additional studies aimed at closing the gap between neuropathology and usable outcome measures would support more accurate subject selection, assessment of target engagement and evaluation of therapeutic efficacy.
Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares ...that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.
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•Inflammation and joint pathology during gout flare is prevented by ketogenic diet•BHB inhibits IL-1β secretion from neutrophils•Ketogenic diet and BHB inhibit NLRP3 activation in aged neutrophils•BHB inhibits both priming and assembly steps of NLRP3 activation in neutrophils
NLRP3 inflammasome activation in macrophages and neutrophils drives painful inflammation during gout. Goldberg et al. report that ketogenic diet prevents systemic inflammation and joint damage in a rat model of gouty flare. Mechanistically, the ketone body β-hydroxybutyrate, the most abundant ketone in vivo, inhibits NLRP3/caspase-1-dependent IL-1β secretion from neutrophils.
Translation of disease-modifying therapies in neurodegenerative disease has been disappointing. Parkinson's disease (PD) was used to compare patterns of preclinical study design for symptomatic and ...potentially disease-modifying interventions. We examined the relationship of model, intervention type and timing, outcomes and outcome measures in 543 animal and human studies (1973-2015) across a contemporary cohort of animal and human interventional studies (n = 445), animal studies for approved interventions (n = 28), animal and human studies for those that failed to translate (n = 70). Detailed study design data were collected for 216 studies in non-human primate (NHP) and rodent toxin-induced models. Species-specific patterns of study design prevailed regardless of whether interventions were symptomatic or potentially disease-modifying. In humans and NHPs, interventions were typically given to both sexes well after the PD phenotype was established, and clinical outcome measures were collected at single (symptomatic) or multiple (disease-modifying) time-points. In rodents, interventions often preceded induction of the model, acute toxic protocols were common, usually given to young males, clinical outcome measures were used less commonly, and outcomes were less commonly assessed at multiple time points. These patterns were more prevalent in mice than rats. In contrast, study design factors such as randomization and blinding did not differ appreciably across symptomatic and disease-modifying intervention categories. The translational gap for potentially disease-modifying interventions in PD in part results from study designs, particularly in mice, that fail to model the progressive nature and relatively late intervention characteristic of PD, or that anchor mechanistic and neuropathologic data to longitudinal clinical outcomes. Even if measures to improve reproducibility are broadly adopted, perpetuation of these norms will continue to impede effective translation.
At present, global immunity to SARS-CoV-2 resides within a heterogeneous combination of susceptible, naturally infected and vaccinated individuals. The extent to which viral shedding and transmission ...occurs on re-exposure to SARS-CoV-2 is an important determinant of the rate at which COVID-19 achieves endemic stability. We used Sialodacryoadenitis Virus (SDAV) in rats to model the extent to which immune protection afforded by prior natural infection via high risk (inoculation; direct contact) or low risk (fomite) exposure, or by vaccination, influenced viral shedding and transmission on re-exposure. On initial infection, we confirmed that amount, duration and consistency of viral shedding, and seroconversion rates were correlated with exposure risk. Animals were reinfected after 3.7-5.5 months using the same exposure paradigm. 59% of seropositive animals shed virus, although at lower amounts. Previously exposed seropositive reinfected animals were able to transmit virus to 25% of naive recipient rats after 24-hour exposure by direct contact. Rats vaccinated intranasally with a related virus (Parker's Rat Coronavirus) were able to transmit SDAV to only 4.7% of naive animals after a 7-day direct contact exposure, despite comparable viral shedding. Cycle threshold values associated with transmission in both groups ranged from 29-36 cycles. Observed shedding was not a prerequisite for transmission. Results indicate that low-level shedding in both naturally infected and vaccinated seropositive animals can propagate infection in susceptible individuals. Extrapolated to COVID-19, our results suggest that continued propagation of SARS-CoV-2 by seropositive previously infected or vaccinated individuals is possible.
Abstract
The Coronavirus Disease 2019 (COVID-19) pandemic has fueled unprecedented development of animal models to understand disease pathogenesis, test therapeutics, and support vaccine development. ...Models previously developed to study severe acute respiratory syndrome coronavirus (SARS-CoV) have been rapidly deployed to study SARS-CoV-2. However, it has become clear that despite the common use of ACE2 as a receptor for both viruses, the host range of the 2 viruses does not entirely overlap. Distinct ACE2-interacting residues within the receptor binding domain of SARS-CoV and SARS-CoV-2, as well as species differences in additional proteases needed for activation and internalization of the virus, are likely sources of host differences between the 2 viruses. Spontaneous models include rhesus and cynomolgus macaques, African Green monkeys, hamsters, and ferrets. Viral shedding and transmission studies are more frequently reported in spontaneous models. Mice can be infected with SARS-CoV; however, mouse and rat ACE2 does not support SARS-CoV-2 infection. Murine models for COVID-19 are induced through genetic adaptation of SARS-CoV-2, creation of chimeric SARS-CoV and SARS-CoV-2 viruses, use of human ACE2 knock-in and transgenic mice, and viral transfection of wild-type mice with human ACE2. Core aspects of COVID-19 are faithfully reproduced across species and model. These include the acute nature and predominantly respiratory source of viral shedding, acute transient and nonfatal disease with a largely pulmonary phenotype, similar short-term immune responses, and age-enhanced disease. Severity of disease and tissue involvement (particularly brain) in transgenic mice varies by promoter. To date, these models have provided a remarkably consistent template on which to test therapeutics, understand immune responses, and test vaccine approaches. The role of comorbidity in disease severity and the range of severe organ-specific pathology in humans remains to be accurately modeled.
•448 interventions across 752 human and animal studies for Alzheimer's disease were compared.•A networks-based systems biology approach was used to assess repeatability of outcomes across species by ...intervention and mechanism.•This approach supports in silico reduction of positive outcomes bias in animal studies.
For many chronic diseases, translational success using the animal model paradigm has reached an impasse. Using Alzheimer's disease as an example, this review employs a networks-based method to assess repeatability of outcomes across species, by intervention and mechanism. Over 75% of animal studies reported an improved outcome. Strain background was a significant potential confounder. Five percent of interventions had been tested across animals and humans, or examined across three or more animal models. Positive outcomes across species emerged for donepezil, memantine and exercise. Repeatable positive outcomes in animals were identified for the amyloid hypothesis and three additional mechanisms. This approach supports in silico reduction of positive outcomes bias in animal studies.
Abstract
Developing strong animal models is essential for furthering our understanding of how the immune system functions in response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) ...infection. The alarming speed at which SARS-CoV-2 has spread, and the high mortality rate of severe Coronavirus Disease 2019 (COVID-19), has required both basic science and clinical research to move at an unprecedented pace. Models previously developed to study the immune response against SARS-CoV have been rapidly deployed to now study SARS-CoV-2. To date, both small and large animal models are remarkably consistent when infected with SARS-CoV-2; however, certain models have proven more useful when answering specific immunological questions than others. Small animal models, such as Syrian hamsters, ferrets, and mice carrying the hACE2 transgene, appear to reliably recapitulate the initial cytokine surge seen in COVID-19 as well as show significant innate and adaptive cell infiltration in to the lung early in infection. Additionally, these models develop strong antibody responses to the virus, are protected from reinfection, and genetically modified versions exist that can be used to ask specific immunological questions. Large animal models such as rhesus and cynomologus macaques and African green monkeys are critical to understanding how the immune system responds to SARS-CoV-2 infection because they are considered to be the most similar to humans. These models are considered the gold standard for assessing vaccine efficacy and protection, and recapitulate the initial cytokine surge, immune cell infiltration into the lung, certain aspects of thrombosis, and the antibody and T-cell response to the virus. In this review, we discuss both small and large animal model studies previously used in SARS-CoV-2 research that may be useful in elucidating the immunological contributions to hallmark syndromes observed with COVID-19.
Discovery studies in animals constitute a cornerstone of biomedical research, but suffer from lack of generalizability to human populations. We propose that large-scale interrogation of these data ...could reveal patterns of animal use that could narrow the translational divide. We describe a text-mining approach that extracts translationally useful data from PubMed abstracts. These comprise six modules: species, model, genes, interventions/disease modifiers, overall outcome and functional outcome measures. Existing National Library of Medicine natural language processing tools (SemRep, GNormPlus and the Chemical annotator) underpin the program and are further augmented by various rules, term lists, and machine learning models. Evaluation of the program using a 98-abstract test set achieved F1 scores ranging from 0.75-0.95 across all modules, and exceeded F1 scores obtained from comparable baseline programs. Next, the program was applied to a larger 14,481 abstract data set (2008-2017). Expected and previously identified patterns of species and model use for the field were obtained. As previously noted, the majority of studies reported promising outcomes. Longitudinal patterns of intervention type or gene mentions were demonstrated, and patterns of animal model use characteristic of the Parkinson's disease field were confirmed. The primary function of the program is to overcome low external validity of animal model systems by aggregating evidence across a diversity of models that capture different aspects of a multifaceted cellular process. Some aspects of the tool are generalizable, whereas others are field-specific. In the initial version presented here, we demonstrate proof of concept within a single disease area, Parkinson's disease. However, the program can be expanded in modular fashion to support a wider range of neurodegenerative diseases.
Despite tremendous investment and preclinical success in neurodegenerative disease, effective disease-altering treatments for patients have remained elusive. One highly cited reason for this ...discrepancy is flawed animal study design and reporting. If this can be broadly remedied, reproducibility of preclinical studies will improve. However, without concurrent efforts to improve generalizability, these improvements may not translate effectively from animal experiments to more complex human neurodegenerative diseases. Mechanistic and phenotypic variability of neurodegenerative disease is such that most models are only able to interrogate individual aspects of complex phenomena. One approach is to consider animals as models of individual targets rather than as models of individual diseases and to migrate the concept of predictive validity from the individual model to the body of experiments that demonstrate translatability of a target. Both exploratory and therapeutic preclinical studies are dependent upon study design methods that promote rigor and reproducibility. However, the body of evidence that is needed to demonstrate efficacy in therapeutic studies is substantially broader than that needed for exploratory studies. In addition to requiring rigor within individual experiments, convincing evidence for therapeutic potential must assess the relationships between model choice, intended goal of the intervention, pharmacologic criteria, and integration of biomarker data with outcome measures that are clinically relevant to humans. It is conceivable that proof-of-concept studies will migrate to cell-based systems and that animal systems will be increasingly reserved for more distal translational purposes. If this occurs, it is likely to prompt reexamination of what the term "translational" truly means.
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