Useful animal models of disease in neuroscience can make accurate predictions about a therapeutic outcome, a feature known as predictive validity. In this issue of the JCI, Knowland et al. provide an improved model to assess nicotinic acetylcholine receptor (nAChR) ligands for treating chronic pain. The authors identify two proteins, the voltage-dependent calcium channel auxiliary subunit BARP and the unfolded protein response sensor IRE1α, that are required for robust heterologous expression of α6β4, an nAChR subtype in dorsal root ganglia (DRG). This nAChR is a candidate for the analgesic effects of nicotine as well as the frog toxin epibatidine. Now researchers can efficiently screen for α6β4 nAChR–selective agonists using heterologous expression systems. Candidates that emerge will enable researchers to test the predictive validity of mouse models for chronic pain in the nAChR context. If all these steps work, one can envision a class of non-opioid nAChR-targeted analgesics for chronic pain.
Stephen Grant, Henry A. Lester
Cytoplasmic aggregated proteins are a common neuropathological feature of neurodegenerative diseases. Cytoplasmic mislocalization and aggregation of TAR-DNA binding protein 43 (TDP-43) is found in the majority of patients with amyotrophic lateral sclerosis (ALS) and in approximately 50% of patients dying of frontotemporal lobar degeneration (FTLD). In this issue of the JCI, Prudencio, Humphrey, Pickles, and colleagues investigated the relationship of TDP-43 pathology with the loss of stathmin-2 (STMN2), an essential protein for axonal growth and maintenance. Comparing genetic, cellular, and neuropathological data from patients with TDP-43 proteinopathies (ALS, ALS–frontotemporal dementia [ALS-FTD], and FTLD-TDP-43 [FTLD-TDP]) with data from patients with non-TDP–related neurodegenerations, they demonstrate a direct relationship between TDP-43 pathology and STMN2 reduction. Loss of the normal transcription suppressor function of TDP-43 allowed transcription of an early termination cryptic axon, resulting in truncated, nonfunctional mRNA. The authors suggest that measurement of truncated STMN2 mRNA could be a biomarker for discerning TDP proteinopathies from other pathologies.
Jonathan D. Glass
Human antibody responses to severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) hold intense interest with research efforts directed at optimizing antibody-based interventions and monitoring immune status. By relating individual variations in antibody response to coronavirus disease 2019 (COVID-19) severity, beneficial antiviral immune responses may be identified in detail. In this issue of the JCI, Secchi and collaborators describe antibody response profiles in 509 COVID-19 patients from Italy during the 2020 pandemic. The research team found that multiple antibody types to multiple SARS-CoV-2 antigens developed over four weeks. Notably, IgG against the spike receptor binding domain (RBD) was predictive of survival and IgA against the viral spike protein (S protein) associated with rapid virologic clearance. These results may help guide selection of convalescent plasma, hyperimmune products, monoclonal antibodies, and vaccine strategies for COVID-19.
Jeffrey P. Henderson
COVID-19 spans and wide range of symptoms, sometimes with profound immune system involvement. How immune cell subsets change during the disease course and with disease severity needs further study. While myeloid cells have been shown to initiate and maintain responses to pneumonia and lung inflammation, often playing a role in resolution, their involvement with COVID-19 remains unknown. In this issue of the JCI, Sánchez-Cerrillo and Pedro-Landete et al. investigated dendritic cells and monocytes from blood and bronchial secretions of patients with varying COVID-19 severity and with healthy controls. The authors conclude that circulating monocytes and DCs migrate from the blood into the inflamed lungs. While sampling differences in sex, collection timing, bacteria/fungal infection, and corticosteroid treatment limit interpretation, we believe that reprograming monocyte or macrophages by targeting immunometabolism, epigenetics, or the cytokine milieu holds promise in resolving lung-inflammation associated with COVID-19.
Franco R. D'Alessio, Nicola M. Heller
Antiretroviral therapy (ART) generally reduces plasma HIV to undetectable levels, although virus persists in latently infected CD4+ T cells. In some individuals, viremia remains detectable despite adherence to ART and the absence of drug resistance mutations. In this issue of the JCI, Halvas et al. describe HIV RNA sequences from plasma of 8 donors with persistent viremia. Residual viremia was dominated by identical HIV-1 RNA sequences that remained relatively constant over 4 years. Plasma virus matched replication-competent virus cultured from CD4+ T cells. Integration site analysis confirmed the presence of large clones of infected cells. These results indicate that nonsuppressible viremia can be due to expanded clones of infected CD4+ T cells carrying replication-competent virus. The individuals described here represent extreme examples of a phenomenon that is seen in all infected individuals and that is a major barrier to curing HIV infection, the in vivo proliferation of latently infected cells.
Janet D. Siliciano, Robert F. Siliciano
Growth hormone–secreting (GH-secreting) pituitary tumors are driven by oncogenes that induce cAMP signaling. In this issue of the JCI, Ben-Shlomo et al. performed a whole-exome study of pituitary adenomas. GH-secreting tumors had a high frequency of whole chromosome or chromosome arm copy number alterations and were associated with an increase in the tumor protein p53 and the cyclin-dependent kinase inhibitor p21WAF1/CIP1, which are findings consistent with induction of a response to DNA damage. Further, treatment of mouse pituitary cells with cAMP pathway agonists in vitro and in vivo elicited biomarkers of DNA replication stress or double-strand breaks. The findings of Ben Shlomo et al. indicate that oncoproteins that drive constitutively high cAMP signaling pathway output in susceptible cell types can elicit DNA replication stress and may promote genomic instability.
James A. Fagin, John H. Petrini
Tuberculosis (TB) continues to affect over 10 million people per year worldwide. Despite advances in diagnosis, smear microscopy insufficiently detects pulmonary disease, with test result reporting taking longer than a day. While urine assays to detect the lipopolysaccharide lipoarabinomannan (LAM), present in mycobacterial cell walls, can provide results within minutes, the currently available assay has low sensitivity and its application is limited to patients with HIV suspected of having TB. In this issue of the JCI, Broger and Nicol et al. investigated 3 rapid urine tests in 372 ambulatory HIV-negative individuals suspected of having TB in South Africa and Peru. FujiLAM emerged as a 25-minute test to confirm TB diagnosis in the HIV-seronegative population. This study shows that FujiLAM has considerable potential to reshape the TB diagnostics landscape, making diagnosis and treatment in one office visit a reality for TB.
Elisa H. Ignatius, Keira A. Cohen, William R. Bishai
While corticosteroids dampen the dysregulated immune system and sometimes are prescribed as an adjunctive treatment for pneumonia, their effectiveness in the treatment of coronavirus 2019 (COVID-19) remains controversial. In this issue of the JCI, Liu and Zhang et al. evaluated corticosteroid treatment in more than 400 patients with severe COVID-19. The authors assessed subjects retrospectively for cardiac and liver injury, shock, ventilation, mortality, and viral clearance. Corticosteroids in severe COVID-19 related acute respiratory distress syndrome (ARDS) was associated with increased mortality and delayed viral clearance. Here, we consider how to reconcile the negative effects of corticosteroids revealed by Liu and Zhang et al. with the favorable effects (reduced mortality) that were described in the RECOVERY trial. We posit that treatment timing, dosage, and COVID-19 disease severity determine immune response and viral outcome. Patients with moderate-to-severe COVID-19 pneumonia are likely to benefit from moderate dose corticosteroid treatment when administered relatively late in the disease course.
Michael A. Matthay, Katherine D. Wick
The disease spectrum of coronavirus disease 2019 (COVID-19) ranges from no symptoms to multisystem failure and death. Characterization of virus-specific immune responses to severe acute respiratory coronavirus 2 (SARS-CoV-2) is key to understanding disease pathogenesis, but few studies have evaluated T cell immunity. In this issue of the JCI, Sattler et al. sampled blood from subjects with COVID-19 and analyzed the activation and function of virus antigen-specific CD4+ T cells. T cells that failed to respond to peptides from the membrane, spike or nucleocapsid proteins were more common in subjects who died. In those whose T cells had the capacity to respond, older patients with more co-morbidity had larger numbers of activated T cells compared with patients that had fewer risk factors, but these cells showed impaired IFN- production. This cross-sectional study relates activated T cell responses to patient risk factors and outcome. However, T cell response trajectory over the disease course remains an open question.
Diane E. Griffin
Allergic disorders include food allergy, allergic rhinitis, and certain forms of asthma resulting from the inappropriate development of immune responses to otherwise innocuous aeroallergens and foods. In this issue of the JCI, Thouvenot and Roitel et al. explore transcription infidelity as a mechanism that underlies the ability of these benign proteins to become allergens. Some foods and bioaerosols that produce allergies have RNA polymerase with a propensity to generate RNA gaps, thereby causing translational frameshifts. These frameshifts often create cationic carboxy-terminus residues that replace hydrophobic amino acids and have enhanced MHC binding, resulting in the tendency to provoke immune responses. IgE antibody responses initiated by these variant transcripts can later lead to IgE against the native molecule and also explain how anaphylaxis may occur in individuals who lacked specific IgE when tested using native protein reagents. This study has the potential to transform the diagnosis and treatment of allergic disorders.
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