TABLE 1.

The roles of insulin and leptin in central nervous system (CNS) infection.

Pathogen/host	Study design and outcome measures	Findings	Proposed direction of causality and/or mechanism	References
Borna disease virus (BDV)
BDV/mouse	Animal model: virus-induced obesity model using intracerebral injection of BDV-1 in rats. Outcome measures: neuropathology including inflammatory infiltrates and neurodegeneration in the hypothalamus, hippocampal shrinkage, and leptin resistance	BDV infection-induced obesity was associated with: 1. hypothalamic inflammation. 2. Hippocampal involution and microglial activation in the neocortex. 3. Preferential infection of glutamatergic sites, while sparing GABAergic areas, causing (anabolic appetite-stimulating) GABAergic predominance and fat accumulation 4. Leptin resistance in the brain.	CNS infection → Hypothalamic inflammation, neurotransmitter imbalance (GABA predominance), obesity, and leptin resistance.	Gosztonyi et al., 2020
BDV/rat	Animal model: BDV infection models using two different strains: BDV-ob (obesity-inducing) and BDV-bi (no obesity-inducing effect). Outcome measures: Mononuclear infiltrates into the brain, astrogliosis, and neuronal death.	1. BDV-ob infection and mononuclear infiltrates were restricted to certain brain areas including hypothalamus, hippocampus, and amygdala. Particularly severe infiltration in the median eminence of hypothalamus. (BDV-ob infection was observed evenly throughout the brain.) 2. Mononuclear infiltrates, astrogliosis, and neuronal death in the hippocampus of BDV-ob infected brain.	CNS infection →Hypothalamic inflammation and disruption of neuroendocrine system →Obesity	Herden et al., 2000
Canine distemper virus (CDV)
CDV/mouse	Metabolic disturbance: obesity induced by intracerebral CDV infection. Outcome measures: Plasma insulin and lipid composition.	Hyperinsulinemia and triglyceride accumulation in CDV-induced obesity mice	CDV infection → Hyperinsulinemia and obesity	Bernard et al., 1988
CDV/mouse	Animal model: obesity induced by intracerebral infection with CDV. Outcome measures: Leptin and LepR expression.	Functional LepR was specifically downregulated in the hypothalamus of obese mice.	CNS infection →Leptin resistance in the hypothalamus. → Obesity.	Bernard et al., 1999
Human immunodeficiency virus (HIV)
HIV/human	Subjects: patients with HIV-1 infection (n203, Cohort study). Outcome measures: association between HIV-associated dementia (HAND) and diabetes.	HAND was significantly associated with diabetes (odds ratio 5.43, 1.66–17.70), which was not fully explained by age or coexisting vascular risk factors.	Diabetes ↔ HAND	Valcour et al., 2005
HIV/mouse	Animal model: HIV model in mice using EcoHIV, with vs. without intranasal insulin treatment (daily for 9 days). Outcome measures: cognitive functions, hippocampal neuronal integrity, and the expression of genes associated with brain functions.	1. Infected mice exhibited cognitive impairment. 2. Intranasal insulin restored cognitive functions, hippocampal dendritic integrity, and gene expressions. 3. The beneficial effect of intranasal insulin was independent of HIV burden in the brain.	Infection →Cognitive impairment. Central insulin treatment → Restoration of brain functions	Kim et al., 2019
HIV/human FIV/cat	1. Human ex vivo model: (1) brain autopsy of patients with HIV/AIDS. (2) HIV-1 infection in primary human neurons and microglia, treated with insulin. Outcome measures: neuroinflammation and neuronal death. 2. Animal in vivo HAND model: feline retrovirus (FIV) intracranial infection in cats. Insulin intranasal treatment for 6 weeks compared to PBS treatment. Outcome measures: morphological changes in the brain, neuroinflammation, neuronal survival, neurobehavioral performance.	1-1. Increased neuroinflammatory gene expression in the brain of HIV/AIDS. 1-2. Insulin treatment suppressed HIV-1 growth and reduced infection-induced CSCL10 and IL-6 expression in HIV-infected microglia. 1-3. Insulin treatment prevented HIV-1 infection-induced neuronal death. 2-1. Insulin treatment enhanced the preservation of cortical neurons, and improved neurobehavioral performance in FIV-infected cats.	Infection → Cognitive impairment. Central insulin treatment → Restoration of brain functions.	Mamik et al., 2016
Porphyromonas gingivalis
P. gingivalis/mouse	Animal model: db/db mouse infected with P. gingivalis (W83, p.o.). Outcome measures: neuroinflammation in the hippocampus; mRNA levels for genes associated with insulin signaling.	1. Infection induced reactive microglia and astrocytes. 2. Infection enhanced the expression of insulin signaling pathway genes (e.g., InsR, Igf1, Irs, and Gsk3β). 3. Pro-inflammatory genes were also up-regulated.	Infection → Disruption of insulin signaling pathway and inflammation in the brain.	Bahar et al., 2021
Toxoplasma gondii
T. gondii/rat	Animal model: T. gondii infection model in rats. Outcome measures: plasma leptin levels	Plasma leptin levels increased in chronic T. gondii infection.	CNS infection → Increase in plasma leptin (metabolic imbalance)	Baltaci and Mogulkoc, 2012
West Nile virus (WNV)
WNV/mouse	Animal model: db/db mouse infected with WNV. Outcome measures: leukocyte infiltration and neuroinflammation/neuronal damage.	Infection-induced leukocyte infiltration into the brain was reduced, while neuroinflammation/neuronal death was enhanced, in db/db mice.	LepR dysfunction → Increased CNS infection susceptibility	Kumar et al., 2014

Relevant keywords, such as insulin and leptin, are highlighted in bold.