Neuroimmune pathophysiology of long COVID -Neuroinvasion :
infecting various cell types, organs, nervous system.Infection of CNS in early phase,brain cells;direct viral infection in brain tissues; perioperative mild to moderate COVID19,CSF from acute & LC onlinelibrary.wiley.com/doi/10.1111/pc… prevalence and extent of direct neuroinvasion is influenced by multiple factors, infection severity viral strain.
SARS-CoV-2 capable of infecting various cell types in the nervous system including neurons, astrocytes, epithelial cells. ACE2 and other coronavirus coreceptors in brain but precise localization of ACE2 within the central nervous system. Neurons derived from human pluripotent stem cells can express ACE2 and facilitate infection in vitro,ACE2 protein is either undetectable in neurons or is localized to discrete nuclei. SARS-CoV-2 can directly infect neurons and disrupt synaptic transmission, by promoting cellular fusion or cellular senescence. extent to which this occurs in human patients is unknown, although direct infection of olfactory bulb and some cortical areas in non-human primates, human and animal studies have reported more robust ACE2 expression in astrocytes, pericytes, endothelial cells of choroid plexus and blood–brain barrier. As SARS-CoV-2 does not appear to be capable of transsynaptic infection within neural circuits,virus preferentially target epithelial cells in the nasal mucosa, choroid plexus, or nervus terminalis neurons in olfactory epithelium, to propagate within nervous system. infection of olfactory neurons in absence of ACE2 expression by formation of tunneling nanotubes between infected epithelial cells and neurons. extent of direct neural infection is strain-specific effects

COVID19: a vascular nightmare unfolding. 1) primary impact of SARSCoV2 infection is on pulmonary system,also implications for vascularity of extrapulmonary system, either through direct viral infection or indirectly through cytokine storms frontiersin.org/journals/immun… 2) COVID19 induces a prethrombotic state (3). Thrombosis of both microvessels and large vessels is prevalent among COVID19 (4) (PE) and (DVT) are freq thrombotic complications in COVID19. Arterial thrombosis is a notable in COVID-19, leading to various complications, such as acute ischemic stroke, acute coronary syndrome (ACS), acute limb ischemia (ALI), mesenteric infarction, renal infarction, spleen infarction

Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID19. with neurological manifestations, categorized into 3 groups: isolated refractory headache; encephalopathy; nature.com/articles/s4159… IND (n = with non-inflammatory, non-infectious neurological conditions as negative controls. Paired CSF and serum samples assessed for 56 biomarkers. Regardless of neurological condition, COVID-19 patients exhib⬆️ CSF levels of proinflammatory mediators, including IL-2, IL-3, IL-6, IL-15, IL-25, IFN-α2, CCL7, CCL11, and GM-CSF. Patients with encephalopathy and IND also show⬆️ IL-1β, IL-18, TNF-α, neopterin, IL-7, CXCL8, CXCL9, TGF-α, EGF, sTREM-2, HMGB1, consistent with a CNS cytokine storm. isolated refractory headache show modest inflammatory profile, compatible with limited CNS involvement. COVID-19 show⬆️ serum IL-13, IL-18, TNF-α, VILIP-1, TGF-α, VEGF levels- systemic inflammation and potential blood–brain barrier (BBB) disruption. β-NGF was⬆️ in CSF with encephalopathy and IND- activation of neuroprotective responses in recovery. Functional protein network analysis show a signif enrichment of interactions between factors altered in CSF with encephalopathy and IND, related to processes of neuroinflammation and microglial functions, leukocyte chemotaxis, activation, proliferation. both systemic immune activation and localized neuroinflammation contribute to the diversity of neurological outcomes in COVID19, dysregulated cytokine production, glial activation, inflammasome activity, BBB disturbances as key factors in neuro-COVID19 pathogenesis.

Antigenic and virological characteristics of SARSCoV2 variants BA.3.2, XFG, NB.1.8.1. Lancet. SARSCoV2 saltation variant BA.3.2, hv > 50 mutations relative to ancestral BA.3 lineage, BA.3.2 exhib 44 mutations distinct from dominant LP.8.1/LP.8.1.1 thelancet.com/journals/lanin… potential to drive an outbreak similar to BA.2.86/JN.1, particularly following its first detection outside South Africa in the Netherlands on April 2, 2025; antigenic profile and infectivity is essential to establish prevailing.

Virological characteristics of SARSCoV2 NB.1.8.1 variant - Lancet Infectious Diseases. SARSCoV2 JN.1, its subvariants, as KP.3 (JN.1.11.1.3) & KP.3.1.1 (JN.1.11.1.3.1.1), & XEC (a recombinant lineage of two JN.1 subvariants),emerged rapidly spread globally thelancet.com/journals/lanin… LP.8.1 (JN.1.11.1.1.1.3.8.1),a descendant lineage of KP.1.1.3 (JN.1.11.1.1.1.3), accounts for 30% of all global infections as of April, 2025; NB.1.8.1 (XDV.1.5.1.1.8.1), descendant lineage of XDV, spread worldwide. XDV is recombinant lineage of XDE

Ischaemic endothelial necroptosis induces haemolysis & COVID19 angiopathy. Microangiopathy is major complication of SARSCoV2 infection-acute & chronic complications of disease; Endotheliopathy & dysregulated blood coagulation prominent in COVID19 nature.com/articles/s4158… microvascular obstruction; extensive endothelial cell (EC) death in microvasculature of COVID19 organs. EC death was not asso with fibrin formation or platelet deposition, but linked to microvascular (RBC) haemolysis. RBC microangiopathy was asso with ischaemia–reperfusion injury

SARSCoV2 nAbs specificities differ dramatically btw recently infected infants & immune-imprinted. nAbs specificities of imprinted vs infants infected with recent strain; biorxiv.org/content/10.110… spike mutations affect neutrz by Abs of adults & children imprinted by original vac vs infants with primary infection by XBB* variant. serum neutralizing activity of imprinted primarily targets spike (RBD), serum neutralizing activity of infants only infected with XBB* mostly targets spike (NTD). In these infants, secondary exposure to XBB* spike via vac shifts more of neutralizing activity towards RBD, specific RBD sites targeted are different than for imprinted adults. dramatic differences in neutralization specificities among with different exposure histories likely impact SARSCoV-2 evolution.

Neutralization of omicron subvariants and antigenic cartography following multiple COVID19 vac & repeated omicron non JN.1 or JN.1 infections; sera from vac-only, hybrid immunity, single or repeated omicron post-vac infections (PVIs),(non-JN.1 & JN.1); nature.com/articles/s4159… neutralization against omicron BA.5, BA.2.75, BQ.1.1, XBB.1.16, XBB.1.5, JN.1. NAbs exhibited a narrow breadth against BA.5 and BA.2.75 and failed to neutralize BQ.1.1 and XBB lineages after 3 to 5 doses of the ancestral monovalent vac. Hybrid immunity elicite⬆️neutralizing titers than vac alone, but titers remain relatively⬇️. A single omicron PVI elicited lower neutralization titers to all variants compared to (WT),

SARS-CoV-2 spike protein long-term effect on neuro-PASC. long COVID/PASC affects at least 10% of all infected, equating 65 million worldwide.Long-COVID/PASC incidence ranges from 50 and 70% in hospitalized & not hospitalized,for 2yr after acute infection frontiersin.org/journals/cellu… 10–12% in vac; Symptoms can persist for up to 2 or 3 years & vary over time; duration of long COVID is extending. 135,161 infected followed for 3 years, a decrease in the number of infected, mortality risk, and PASC was observed over time. While the risk of death diminishes after 1 year in non-hospitalized patients, it persists beyond 3 years in hospitalized patients, along with an increased risk of developing PASC.

Long COVID is not same for everyone:hierarchical cluster analysis of LC symptoms 9 & 12mth after SARSCoV2 test: 552 individuals at 9 months; 458 at 12 months. median age was 52yr & 59% female. Hypertension & high cholesterol were most frequent pre-existing bmcinfectdis.biomedcentral.com/articles/10.11… Memory loss, fatigue or weakness and joint pain were most frequent symptoms reported 9 and 12 months after positive test. 4 clusters were identified at both times: no or minor symptoms; multi-symptoms; joint pain; and neurocognitive-related symptoms. Clusters remained similar in both times, but, within neurocognitive cluster, memory loss and concentration issues increased in frequency at 12 months. Multi-symptoms cluster had older people, more females and more pre-existing health conditions at 9 months. at 12 months, older people and those with more pre-existing health conditions were in joint pain cluster.

The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China -Viral RNA was distributed across ten different types of solid tissues, liver, kidney, stomach, intestine, brain, blood vessel, thelancet.com/journals/lanin… lung, breast, skin, thyroid, subgenomic RNA was detected in (43%) of 61 solid tissue samples tested for subgenomic RNA that also tested positive for viral RNA. At 2 months after infection, viral RNA was detected in plasma of (33%), granulocytes of one (11%),

SARSCoV2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID19; SARSCoV2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) result in⬆️mitochondrial reactive oxygen species (mROS) production. ⬆️mROS stabilizes HIF-1α; sciencedirect.com/science/articl… redirects carbon molecules from mitochondrial oxidation thro glycolysis & pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS induces the release of mitochondrial DNA (mtDNA) which activates innate immunity.

Viral persistence in children infected with SARSCoV2: current evidence and future research strategies: Lancet Microbe:LC who underwent surgery for other reasons 175d & 426d after initial infection had e/o SARSCoV-l2 RNA in breast, appendix, skin. thelancet.com/journals/lanmi… plasma of with or without LC & uninfected controls, show persistence of viral protein in LC concomitant immunological perturbations,proinflammatory & pro-fibrotic cytokines. Viral persistence detected in immunocompromised, persistent virus replicate, evolve, generate new variants

Immune Responses in Discharged COVID19 Patients With/ Without Long COVID Symptoms; 2 groups: LC & CP group. Both groups underwent virus-specific immunological analyses,enzyme-linked immunosorbent,IFN-γ-enzyme-linked immune absorbent, intracellular cytokine academic.oup.com/ofid/article/1… 12mth after infection, 98.5% were seropositive & 93.3% had detectable SARSCoV2-specific mTcells. LC had signif⬆️levels of (RBD)– (IgG) levels, as OD450 values, than CP controls (0.40 vs 0.37 P = .022); magnitude of SARSCoV2-specific Tcell responses didn’t differ signif btw grps

Kidney damage asso with COVID19: from acute to chronic phase; most common form of glomerular injury is collapsing glomerulopathy (CG), strongly asso with apolipoprotein L1(APOL-1) risk variants; acute lesions, are secondary to direct or indirect effects, tandfonline.com/doi/full/10.10… progress to chronicity; specific to long COVID-19 in absence of any other cause. Residual inflammation asso with SARS-CoV-2 infection, add to (AKI) as transitional state with or without severe histological lesions,responsible for greater kidney funct⬇️in mild-to-moderate COVID19

SARSCoV2 infects neurons, induces neuroinflammation in a non-human primate model of COVID-19: SARSCoV-2 is found in olfactory brain areas at 7d post infection;
Neurons are initially primary target of SARSCoV2 productive infection;
cell.com/cell-reports/f… Neurocovid is accompanied by robust neuroinflammation & vascular disruption;
SARSCoV2 brain pathology is worsened by aging & diabetes in infected

COVID-19 Asso CVS Disease;Risks, Prevention, Management: Heart at Risk Due to COVID19; SARSCoV2 belongs to Sarbecovirus lineage of β-CoVs; SARS-CoV-2 shares 79.5% of sequence identity with virus SARSCoV. transmissibility of initial SARSCo2 variant, mdpi.com/1467-3045/46/3… Alpha (B.1.1.7), is estimated to be 10x faster than of SARSCoV virus, result in rapid spread.
SARSCoV2 virus continued to mutate, producing new disease variants character by diff in spike glycoprotein; VOC -beta, delta, recently, omicron strains. omicron variant & subvariants

Long Covid and Impaired Cognition — More Evidence and More Work to Do: Modest cognitive decline occurred with original virus & with each viral variant, B.1.1.529 (omicron). As compared with uninfected (control), nejm.org/doi/full/10.10… cognitive deficit — commensurate with 3-point loss in IQ — evident even in who had had mild Covid19 with resolved symptoms. with unresolved persistent symptoms had equivalent of a 6-point loss in IQ; those admitted to ICU had equivalent of a 9-point loss in IQ.

Insights into attention and memory difficulties in post-COVID syndrome using standardized neuropsychological tests, experimental cognitive tasks; neuropsychological assessment, post-COVID show signif worse performance wrt normative sample on multiple tests nature.com/articles/s4159… assessing attention and executive functions (TMT-B, Stroop, PASAT, MFPT), and naming abilities; average z scores 1 SD lower wrt normative sample on TMT-B and naming tests; Prospective and Retrospective Memory Questionnaire (PRMQ) show⬆️incidence of subjective memory complaints:

Myopericarditis following COVID19 vac & non-COVID19 vac:systematic review meta-analysis: Lancet Respiratory Medicine; overall incidence of myopericarditis from 22 studies (405 272 721 vac doses) was 33·3 cases/million vac doses, thelancet.com/journals/lanre… did not differ signif btw COVID19 vac (18·2, 11 studies [395 361 933 doses]) & non-COVID19 vac (56·0, 11 studies [9 910 788 doses], p=0·20). Compared with COVID19 vac, incidence of myopericarditis was signif⬆️following smallpox vac (132·1, p<0·0001)

Conventional dendritic cell 2 links the genetic causal association from allergic asthma to COVID19: negative causal correlation from AA to COVID19 hospitalization (OR = 0.968, P = 0.031). correlation was bridged thro white cell count, journalofbigdata.springeropen.com/articles/10.11… DCs) as most discriminative immunocytes in AA & COVID19. Among 5 DC subtypes, only conventional dendritic cell 2 (cDC2) exhibited differential expression between AA/COVID19 and controls (P < 0.05), energy metabolism, intercellular communication, cellular stemness,