Persistent Central Nervous System Infection Research Articles

COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications.

To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC). Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed. SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, β2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies. We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation.

Pediatric Research Challenge, Alignment with the National Research Agenda

Pediatric Research Challenge, Alignment with the National Research Agenda

Vaccine-Associated Measles Encephalitis in Immunocompromised Child, California, USA

We report a fatal case of vaccine-associated measles encephalitis in an immunocompromised child in California, USA. The infection was confirmed by whole-genome RNA sequencing of measles virus from brain tissue. We observed biased matrix-gene hypermutation consistent with persistent measles virus central nervous system infection.

Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection.

This study was undertaken to assess whether SARS‐CoV‐2 causes a persistent central nervous system infection. SARS‐CoV‐2–specific antibody index and SARS‐CoV‐2 RNA were studied in cerebrospinal fluid following COVID‐19. Cerebrospinal fluid was assessed between days 1 and 30 (n = 12), between days 31 and 90 (n = 8), or later than 90 days (post–COVID‐19, n = 20) after COVID‐19 diagnosis. SARS‐CoV‐2 RNA was absent in all patients, and in none of the 20 patients with post–COVID‐19 syndrome were intrathecally produced anti–SARS‐CoV‐2 antibodies detected. The absence of evidence of SARS‐CoV‐2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post–COVID‐19 syndrome. ANN NEUROL 2022;91:150–157

Neurological complications of HIV infection

The fact that HIV infection directly impacts the central nervous system (CNS) has been recognized since very early in the global HIV epidemic. The emergence of widespread antiretroviral therapy (ART) use has altered the clinical character of neurologic disease observed in HIV, led to new challenges related to optimization of CNS treatment, and raised a host of questions related to the role of the CNS as a potential barrier to HIV eradication and cure. This presentation will review key issues in this landscape of clinical and scientific issues facing people living with HIV, providers, and investigators in the current era. Potential mechanisms of HIV-related CNS dysfunction observed in patients treated with ART include persistent CNS infection, ongoing immune activation, effect of comorbidities including vascular disease, aging, antiretroviral drug exposure in the CNS associated with either toxicity or inadequate tissue distribution, and neurologic injury accrued prior to initiation of antiretroviral treatment. Related to issues of persistent clinical CNS abnormality in the face of ART, novel research questions are raised by efforts to successfully ‘cure’ HIV: whether the CNS may provide a reservoir for infection which may be a significant impediment to efforts to eradicate HIV. The pathobiology of this putative reservoir is under active investigation, including studies on the timing of establishment of CNS infection, the potential cells and tissues harboring HIV in the CNS, evidence of independent evolution of HIV in the CNS, and the possibility of autonomous CNS sources of HIV replication in the setting of suppressive therapy.

A rare presentation of fulminant subacute sclerosing panencephalitis with acute disseminated encephalomyelitis and meningoencephalitis

Subacute sclerosing panencephalitis (SSPE) is a rare form of chronic progressive neurodegenerative disorder, caused by persistent central nervous system (CNS) infection by hypermutated strains of Measles virus. It primarily affects children and early adolescent age group. Since there is widespread involvement of CNS, the primary symptoms may start with behavior and personality changes with intellectual involvement followed with myoclonic jerks, convulsion, and hemi or quadriparesis. In later stage, the patient may experience dementia, stupor, coma, or death. However, initial presentation can be variable and atypical, making the diagnosis very challenging in clinical practice. Herein, we report a case of fulminant SSPE in a 13-year-old adolescent male who presented with the features of acute disseminated encephalomyelitis (ADEM) and meningoencephalitis. The patient presented in altered sensorium with the history of poor communications, jerky movement of limbs, and fever for 10–14 days. Preliminary investigations were suggestive of meningoencephalitis and ADEM. After initial course of treatment, the patient did not improve, deteriorated further, and succumbed to his illness, a day before we received the conclusive reports for SSPE. As we experienced from our case report, SSPE can create a lot of diagnostic dilemma to the clinicians in such a fulminant presentation, mainly due to limitation of resources, time, and lack of proper vaccination records. The lack of definitive treatment for SSPE once again proved the proverb that “prevention will always be better than cure.”

Latent Toxoplasmosis Effects on Rodents and Humans: How Much is Real and How Much is Media Hype?

Toxoplasma gondii is a ubiquitous, intracellular protozoan parasite with a broad range of intermediate hosts, including humans and rodents. In many hosts, T. gondii establishes a latent long-term infection by converting from its rapidly dividing or lytic form to its slowly replicating and encysting form. In humans and rodents, the major organ for encystment is the central nervous system (CNS), which has led many to investigate how this persistent CNS infection might influence rodent and human behavior and, more recently, neurodegenerative diseases. Given the interest in this topic, here we seek to take a global approach to the data for and against the effects of latent T. gondii on behavior and neurodegeneration and the proposed mechanisms that might underlie behavior modifications.

Henipavirus infection of the central nervous system.

Nipah virus (NiV) and Hendra virus are highly pathogenic zoonotic viruses of the genus Henipavirus, family Paramyxoviridae. These viruses were first identified as the causative agents of severe respiratory and encephalitic disease in the 1990s across Australia and Southern Asia with mortality rates reaching up to 75%. While outbreaks of Nipah and Hendra virus infections remain rare and sporadic, there is concern that NiV has pandemic potential. Despite increased attention, little is understood about the neuropathogenesis of henipavirus infection. Neuropathogenesis appears to arise from dual mechanisms of vascular disease and direct parenchymal brain infection, but the relative contributions remain unknown while respiratory disease arises from vasculitis and respiratory epithelial cell infection. This review will address NiV basic clinical disease, pathology and pathogenesis with a particular focus on central nervous system (CNS) infection and address the necessity of a model of relapsed CNS infection. Additionally, the innate immune responses to NiV infection in vitro and in the CNS are reviewed as it is likely linked to any persistent CNS infection.

The Pathogenesis of Saffold Virus in AG129 Mice and the Effects of Its Truncated L Protein in the Central Nervous System.

Saffold Virus (SAFV) is a human cardiovirus that has been suggested to cause severe infection of the central nervous system (CNS). Compared to a similar virus, Theiler’s murine encephalomyelitis virus (TMEV), SAFV has a truncated Leader (L) protein, a protein essential in the establishment of persistent CNS infections. In this study, we generated a chimeric SAFV by replacing the L protein of SAFV with that of TMEV. We then compared the replication in cell cultures and pathogenesis in a mouse model. We showed that both SAFV and chimeric SAFV are able to infect Vero and Neuro2a cells well, but only chimeric SAFV was able to infect RAW264.7. We then showed that mice lacking IFN-α/β and IFN-γ receptors provide a good animal model for SAFV infection, and further identified the locality of the infection to the ventral horn of the spine and several locations in the brain. Lastly, we showed that neither SAFV nor chimeric SAFV causes persistence in this model. Overall, our results provide a strong basis on which the mechanisms underlying Saffold virus induced neuropathogenesis can be further studied and, hence, facilitating new information about its pathogenesis.

Commentary: Methamphetamine mediates immune dysregulation in a murine model of chronic viral infection

Commentary: Methamphetamine mediates immune dysregulation in a murine model of chronic viral infection

Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein by Proprotein Convertases Modulates Neurovirulence and Virus Spread within the Central Nervous System.

Human coronaviruses (HCoV) are respiratory pathogens that may be associated with the development of neurological diseases, in view of their neuroinvasive and neurotropic properties. The viral spike (S) glycoprotein is a major virulence factor for several coronavirus species, including the OC43 strain of HCoV (HCoV-OC43). In an attempt to study the role of this protein in virus spread within the central nervous system (CNS) and neurovirulence, as well as to identify amino acid residues important for such functions, we compared the sequence of the S gene found in the laboratory reference strain HCoV-OC43 ATCC VR-759 to S sequences of viruses detected in clinical isolates from the human respiratory tract. We identified one predominant mutation at amino acid 758 (from RRSR↓ G 758 to RRSR↓R 758), which introduces a putative furin-like cleavage (↓) site. Using a molecular cDNA infectious clone to generate a corresponding recombinant virus, we show for the first time that such point mutation in the HCoV-OC43 S glycoprotein creates a functional cleavage site between the S1 and S2 portions of the S protein. While the corresponding recombinant virus retained its neuroinvasive properties, this mutation led to decreased neurovirulence while potentially modifying the mode of virus spread, likely leading to a limited dissemination within the CNS. Taken together, these results are consistent with the adaptation of HCoV-OC43 to the CNS environment, resulting from the selection of quasi-species harboring mutations that lead to amino acid changes in viral genes, like the S gene in HCoV-OC43, which may contribute to a more efficient establishment of a less pathogenic but persistent CNS infection. This adaptative mechanism could potentially be associated with human encephalitis or other neurological degenerative pathologies.

Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity.

ABSTRACTThe initiating events in autoimmune disease remain to be completely understood, but it is thought that genetic predisposition synergizes with “environmental” factors, including viral infection, leading to disease. One elegant animal model used to study the pathogenesis of multiple sclerosis that perfectly blends genetics and environmental components in the context of virus-induced autoimmunity is Theiler’s murine encephalitis virus-induced demyelinating disease (TMEV-IDD). TMEV-infected disease-susceptible SJL/J mice develop a persistent central nervous system (CNS) infection and later develop autoimmune demyelination, while disease-resistant C57BL/6 (B6) mice rapidly clear the infection and develop no autoimmune pathology. Mice of the (B6 × SJL/J)F1 cross between these two mouse strains are classified as intermediately susceptible. We employed this model to investigate if rapid virus clearance in B6 versus SJL/J mice was perhaps related to differences in the innate immune response in the CNS of the two strains in the first few days following intracerebral virus inoculation. Here we show that SJL/J mice lack, in addition to NK cells, a novel innate immune subset known as natural killer dendritic cells (NKDCs), which express phenotypic markers (CD11cint NK1.1+) and functional activity of both NK cells and DCs. These NKDCs are activated in the periphery and migrate into the infected CNS in a very late antigen 4 (VLA-4)-dependent fashion. Most significantly, NKDCs are critical for CNS clearance of TMEV, as transfer of NKDCs purified from B6 mice into TMEV-IDD-susceptible (B6 × SJL/J)F1 mice promotes viral clearance. Together the findings of this work show for the first time a link between NKDCs, viral infection, and CNS autoimmunity.

Intraventricular versus intravenous colistin for the treatment of extensively drug resistant Acinetobacter baumannii meningitis.

Reports on the safety and efficacy of intraventricularly administered (IVT) colistin for the treatment of Acinetobacter baumannii ventriculomeningitis in adults are limited and no comparative studies of IVT colistin versus intravenous (IV) therapy alone have been published. This study compared outcomes of patients with postneurosurgical ventriculomeningitis caused by extensively drug-resistant A. baumannii treated with IV colistin or IV plus IVT colistin. In an 11-year period, information on 18 consecutive patients with extensively drug-resistant A. baumannii ventriculomeningitis was collected. Infection was defined on the basis of (i) isolation of A. baumannii from the cerebrospinal fluid (CSF); (ii) laboratory evidence of CSF infection; (iii) signs/symptoms of central nervous system (CNS) infection. Patients were divided into group 1 (nine patients, IV colistin alone) and group 2 (nine patients, IV plus IVT colistin). Cerebrospinal fluid sterilization was documented for 12 of 18 patients (66.6%). The CSF sterilization rate was 33.3% in group 1 and 100% in group 2 (P = 0.009). The mean time to CSF sterilization was 21 days (range 8-48). Five patients died due to A. baumannii CNS infection (all in group 1), and five deaths were unrelated to A. baumannii ventriculomeningitis. Intensive care unit mean length of stay was shorter in group 2 (20.7 vs. 41.6 days, P = 0.046). Crude relative risk ratio of cumulative incidence of persistent CNS infection in group 1 versus group 2 was 13. No cases of chemical meningitis due to intrathecal colistin administration were encountered. Intraventricular colistin administration is much more effective than IV therapy alone and does not seem to add further toxicity.

A Lethal Sequelae of Spinal Infection Complicating Surgery and Radiotherapy for Head and Neck Cancer.

Patients who have undergone neck dissection and radiotherapy are at risk of cervical spine infections. Furthermore, previous radiotherapy and cervical spine infections can lead to fistula formation to the subarachnoid space and intracranial infection. This report discusses the serious consequences of a missed cervical spine infection including cerebrospinal fluid fistula formation and persistent central nervous system infection, and serves as a reminder to clinicians of the possible association between cervical spine infections and prior head and neck surgery and radiotherapy. In all such cases, the posterior pharyngeal wall should be inspected during follow-up. Despite the appearance of an intracranial infection, the cervical spine should be investigated, especially if the response to appropriate antibiotics is suboptimal.

Human herpesvirus types 6 and 7 infection in pediatric hematopoietic stem cell transplant recipients.

The immunosuppressed state in patients undergoing hematopoietic stem cell transplantation (HSCT) predisposes them to activation of latent viral infections such as herpesvirus types 6 and 7 (HHV6 and HHV7). We aimed to evaluate the incidence, manifestations, outcomes, and risk factors of HHV 6 and HHV 7 infections after pediatric hematopoietic stem cell transplantation. We performed 106 HSCTs (86 allogeneic and 20 autologous) on 94 children (56 boys, median age 7.1 years) during 2006-2012. Patients suspected to have HHV6 or HHV7 infections were tested using polymerase chain reaction on serum and/or cerebrospinal fluid. Among the 63 patients tested for HHV, 10 patients (15.9%) were infected (HHV-6 (n=6), HHV-7 (n=4)) at a median of 18 days post-HSCT (cumulative incidence 11.5% at 1 year). Manifestations included fever (90%), rash (70%), hepatitis (80%), pneumonitis (50%), central nervous system (CNS) manifestations (40%), and graft failure (10%). One patient had persistent CNS infection despite treatment with foscarnet, ganciclovir, and cidofovir. Seven patients cleared herpesvirus after a median of 22 days. Four patients died (relapse of malignancy [n=3], acute graft-versus-host disease [aGVHD] [n=1]). Herpesvirus infections were associated with adenovirus infection (p=0.001) and severe (grade III-IV) aGVHD (p=0.037). We concluded that HHV6 and HHV7 infections are common after pediatric HSCT. Most infections were self-limited and could be associated with adenovirus infection and severe aGVHD. Further studies are needed to evaluate predictors of severe morbidity or mortality, and define optimal prophylaxis and treatment.

The Antiapoptotic Protein Mcl-1 Controls the Type of Cell Death in Theiler's Virus-Infected BHK-21 Cells

Theiler's murine encephalomyelitis virus (TMEV) results in a persistent central nervous system infection (CNS) and immune-mediated demyelination in mice. TMEV largely persists in macrophages (Ms) in the CNS, and infected Ms in vitro undergo apoptosis, whereas the infection of other rodent cells produces necrosis. We have found that necrosis is the dominant form of cell death in BeAn virus-infected BHK-21 cells but that ~20% of cells undergo apoptosis. Mcl-1 was highly expressed in BHK-21 cells, and protein levels decreased upon infection, consistent with onset of apoptosis. In infected BHK-21 cells in which Mcl-1 expression was knocked down using silencing RNAs there was a 3-fold increase in apoptotic cell death compared to parental cells. The apoptotic program switched on by BeAn virus is similar to that in mouse Ms, with hallmarks of activation of the intrinsic apoptotic pathway in a tumor suppressor protein p53-dependent manner. Infection of stable Mcl-1-knockdown cells led to restricted virus titers and increased physical to infectious particle (PFU) ratios, with additional data suggesting that a late step in the viral life cycle after viral RNA replication, protein synthesis, and polyprotein processing is affected by apoptosis. Together, these results indicate that Mcl-1 acts as a critical prosurvival factor that protects against apoptosis and allows high yields of infectious virus in BHK-21 cells.

Prolonged triple therapy for persistent multidrug-resistantAcinetobacter baumanniiventriculitis

A case of persistent multidrug-resistant (MDR) Acinetobacter baumannii ventriculitis successfully treated with a prolonged and novel combination of antimicrobials is reported. A 38-year-old, 84-kg Caucasian woman with a recent history of craniotomy was admitted with nausea, fever, headache, photophobia, and drainage from her craniotomy incision. She underwent a repeat craniotomy on hospital day 4 with abscess debridement and repair of a cerebrospinal fluid leak. Cultures grew MDR A. baumannii, coagulase-negative Staphylococcus species, and methicillin-resistant Staphylococcus aureus. Based on the limited published pharmacokinetic and pharmacodynamic data for colistin, we determined a favorable outcome with i.v. colistin monotherapy was unlikely and decided to treat the patient with simultaneous i.v. and intraventricular colistin, as well as intraventricular tobramycin and i.v. rifampin. She was treated with a total of 36 days of intraventricular colistin, 40 days of intraventricular tobramycin, 51 days of i.v. colistin and rifampin, and 56 days i.v. vancomycin for infection that persisted despite multiple debridements. The patient had subsequent improvement in clinical manifestations and eradication of infection. She was subsequently discharged to an acute rehabilitation facility on hospital day 77 with posttreatment sequelae including mental impairment and renal failure requiring hemodialysis. Follow-up visits revealed significant improvement in her mental status, speech, and strength on the side not affected by the stroke. Prolonged combination therapy with intraventricular colistin and tobramycin plus i.v. colistin, rifampin, and vancomycin led to the resolution of a persistent central nervous system infection caused by MDR A. baumannii.

Dynamics of memory T cells clearing a persistent CNS infection in the absence of severe tissue injury (53.9)

Abstract Many viruses can infect the mammalian central nervous system (CNS), some with devastating consequences, and others with little or no overt pathology. Immunotherapy is a successful approach to treat persistent infections that has shown promise in humans. Our laboratory studies a murine model of persistent lymphocytic choriomeningitis virus (LCMV) infection to understand the mechanism(s) by which immunotherapy with virus-specific memory T cells cleanses the infected CNS with minimal cellular damage and blood brain barrier breakdown. Using two-photon microscopy, we observed that therapeutic memory T cells invade the meninges and brain parenchyma, scanning both areas systemically for viral antigen. Interestingly, T cell surveillance of the persistently infected brain was not associated with massive recruitment of peripheral myelomonocytic cells - innate cells known to cause severe vascular pathology during LCMV meningitis. Instead, we revealed using CD11c-YFP reporter mice that immunotherapeutic T cells transformed microglia into a DC phenotype, inducing CD11c expression on microglia throughout the brain parenchyma. Microglia also participated in immunotherapy by directly releasing chemokines such as CCL5. We propose that successful clearance of a persistently infected brain can be achieved without induction of severe tissue injury by tailoring chemokine release to limit myelomonocytic cell recruitment and by converting microglia into local antigen presenting cells.

Theiler's Murine Encephalomyelitis Virus L* Amino Acid Position 93 Is Important for Virus Persistence and Virus-Induced Demyelination

The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) induce a persistent central nervous system infection associated with an inflammatory white matter demyelinating disease. TO subgroup strains synthesize an 18-kDa protein, L*, out of frame with the polyprotein from an initiation codon 13 nucleotides downstream from the polyprotein's AUG codon. We previously generated a mutant virus from our infectious DA full-length clone that has a change of the L* AUG codon to ACG (with no change in the polyprotein's amino acid sequence). Studies of this mutant virus showed that L* was key to the TO subgroup phenotype because the mutant had a decreased ability to persist and demyelinate. This work was initially called into question because a similar mutant derived from a different full-length DA infectious clone persisted and demyelinated similarly to wild-type DA virus (O. van Eyll and T. Michiels, J. Virol. 74:9071-9077, 2000). We now report that (i) the sequence of the L* coding region differs in the two infectious clones, resulting in a Ser or Leu as the predicted amino acid at position 93 of L* (with no change in the polyprotein's amino acid sequence), (ii) the difference in this amino acid is key to the phenotypic differences between the two mutants, and (iii) the change in amino acid 93 may affect L* phosphorylation. It is of interest that this amino acid only appears critical in determining the virus phenotype when L* is present in a significantly reduced amount (i.e., following translation from an ACG initiating codon).

A Subgenomic Segment of Theiler's Murine Encephalomyelitis Virus RNA Causes Demyelination

The DA strain of Theiler's murine encephalomyelitis virus (TMEV) causes a persistent central nervous system (CNS) infection of mice with a restricted virus gene expression and induces an inflammatory demyelinating disease that is thought to be immune mediated and a model of multiple sclerosis (MS). The relative contribution of virus vis-à-vis the immune system in the pathogenesis of DA-induced white matter disease remains unclear, as is also true in MS. To clarify the pathogenesis of DA-induced demyelination, we used Cre/loxP technology to generate a transgenic mouse that has tamoxifen (Tm)-inducible expression of a subgenomic segment of DA RNA in oligodendrocytes and Schwann cells. Tm-treated young transgenic mice developed progressive weakness leading to death, with abnormalities of oligodendrocytes and Schwann cells and demyelination, but without inflammation, demonstrating that DA virus can play a direct pathogenic role in demyelination. Tm treatment of mice at a later age resulted in milder disease, with evidence of peripheral nerve remyelination and focal fur depigmentation; surviving weak mice had persistent expression of the recombined transgene in the CNS, suggesting that the DA subgenomic segment can cause cellular dysfunction but not death, possibly similar to the situation seen during DA virus persistence. These studies demonstrate that DA RNA or a DA protein(s) is toxic to myelin-synthesizing cells. This Cre/loxP transgenic system allows for spatially and temporally controlled expression of the viral transgene and is valuable for clarifying nonimmune (and immune) mechanisms of demyelination induced by TMEV as well as other viruses.