Neurocognitive patterns across genetic levels in behavioral variant frontotemporal dementia: a multiple single cases study.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) has been related to different genetic factors. Identifying multimodal phenotypic heterogeneity triggered by various genetic influences is critical for improving diagnosis, prognosis, and treatments. However, the specific impact of different genetic levels (mutations vs. risk variants vs. sporadic presentations) on clinical and neurocognitive phenotypes is not entirely understood, specially in patites from underrepresented regions such as Colombia. METHODS: Here, in a multiple single cases study, we provide systematic comparisons regarding cognitive, neuropsychiatric, brain atrophy, and gene expression-atrophy overlap in a novel cohort of FTD patients (n = 42) from Colombia with different genetic levels, including patients with known genetic influences (G-FTD) such as those with genetic mutations (GR1) in particular genes (MAPT, TARDBP, and TREM2); patients with risk variants (GR2) in genes associated with FTD (tau Haplotypes H1 and H2 and APOE variants including ε2, ε3, ε4); and sporadic FTD patients (S-FTD (GR3)). RESULTS: We found that patients from GR1 and GR2 exhibited earlier disease onset, pervasive cognitive impairments (cognitive screening, executive functioning, ToM), and increased brain atrophy (prefrontal areas, cingulated cortices, basal ganglia, and inferior temporal gyrus) than S-FTD patients (GR3). No differences in disease duration were observed across groups. Additionally, significant neuropsychiatric symptoms were observed in the GR1. The GR1 also presented more clinical and neurocognitive compromise than GR2 patients; these groups, however, did not display differences in disease onset or duration. APOE and tau patients showed more neuropsychiatric symptoms and primary atrophy in parietal and temporal cortices than GR1 patients. The gene-atrophy overlap analysis revealed atrophy in regions with specific genetic overexpression in all G-FTD patients. A differential family presentation did not explain the results. CONCLUSIONS: Our results support the existence of genetic levels affecting the clinical, neurocognitive, and, to a lesser extent, neuropsychiatric presentation of bvFTD in the present underrepresented sample. These results support tailored assessments characterization based on the parallels of genetic levels and neurocognitive profiles in bvFTD.

TLR4 signaling improves PD-1 blockade therapy during chronic viral infection.

CD8 T cells are necessary for the elimination of intracellular pathogens, but during chronic viral infections, CD8 T cells become exhausted and unable to control the persistent infection. Programmed cell death-1 (PD-1) blockade therapies have been shown to improve CD8 T cell responses during chronic viral infections. These therapies have been licensed to treat cancers in humans, but they have not yet been licensed to treat chronic viral infections because limited benefit is seen in pre-clinical animal models of chronic infection. In the present study, we investigated whether TLR4 triggering could improve PD-1 therapy during a chronic viral infection. Using the model of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, we show that TLR4 triggering with sublethal doses of lipopolysaccharide (LPS) followed by PD-1 blockade results in superior improvement in circulating virus-specific CD8 T cell responses, relative to PD-1 blockade alone. Moreover, we show that the synergy between LPS and PD-1 blockade is dependent on B7 costimulation and mediated by a dendritic cell (DC) intrinsic mechanism. Systemic LPS administration may have safety concerns, motivating us to devise a safer regimen. We show that ex vivo activation of DCs with LPS, followed by adoptive DC transfer, results in a similar potentiation of PD-1 therapy without inducing wasting disease. In summary, our data demonstrate a previously unidentified role for LPS/TLR4 signaling in modulating the host response to PD-1 therapy. These findings may be important for developing novel checkpoint therapies against chronic viral infection.

Broad detection of bacterial type III secretion system and flagellin proteins by the human NAIP/NLRC4 inflammasome.

Inflammasomes are cytosolic multiprotein complexes that initiate host defense against bacterial pathogens by activating caspase-1-dependent cytokine secretion and cell death. In mice, specific nucleotide-binding domain, leucine-rich repeat-containing family, apoptosis inhibitory proteins (NAIPs) activate the nucleotide-binding domain, leucine-rich repeat-containing family, CARD domain-containing protein 4 (NLRC4) inflammasome upon sensing components of the type III secretion system (T3SS) and flagellar apparatus. NAIP1 recognizes the T3SS needle protein, NAIP2 recognizes the T3SS inner rod protein, and NAIP5 and NAIP6 recognize flagellin. In contrast, humans encode a single functional NAIP, raising the question of whether human NAIP senses one or multiple bacterial ligands. Previous studies found that human NAIP detects both flagellin and the T3SS needle protein and suggested that the ability to detect both ligands was achieved by multiple isoforms encoded by the single human NAIP gene. Here, we show that human NAIP also senses the Salmonella Typhimurium T3SS inner rod protein PrgJ and that T3SS inner rod proteins from multiple bacterial species are also detected. Furthermore, we show that a single human NAIP isoform is capable of sensing the T3SS inner rod, needle, and flagellin. Our findings indicate that, in contrast to murine NAIPs, promiscuous recognition of multiple bacterial ligands is conferred by a single human NAIP.

Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARS-CoV-2 Nucleocapsid protein.

Introduction: Many people with long COVID symptoms suffer from debilitating neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). Although symptoms of Neuro-PASC are widely documented, it is still unclear whether PASC symptoms impact virus-specific immune responses. Therefore, we examined T cell and antibody responses to SARS-CoV-2 Nucleocapsid protein to identify activation signatures distinguishing Neuro-PASC patients from healthy COVID convalescents. Results: We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated CD4+ T cell responses and diminished CD8+ memory T cell activation toward the C-terminal region of SARS-CoV-2 Nucleocapsid protein when examined both functionally and using TCR sequencing. CD8+ T cell production of IL-6 correlated with increased plasma IL-6 levels as well as heightened severity of neurologic symptoms, including pain. Elevated plasma immunoregulatory and reduced pro-inflammatory and antiviral response signatures were evident in Neuro-PASC patients compared with COVID convalescent controls without lasting symptoms, correlating with worse neurocognitive dysfunction. Discussion: We conclude that these data provide new insight into the impact of virus-specific cellular immunity on the pathogenesis of long COVID and pave the way for the rational design of predictive biomarkers and therapeutic interventions.

Corrigendum: Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARSCoV-2 Nucleocapsid protein.

[This corrects the article DOI: 10.3389/fimmu.2023.1155770.].

Adoptive B cell therapy for chronic viral infection.

T cell-based therapies have been widely explored for the treatment of cancer and chronic infection, but B cell-based therapies have remained largely unexplored. To study the effect of B cell therapy, we adoptively transferred virus-specific B cells into mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). Adoptive transfer of virus-specific B cells resulted in increase in antibody titers and reduction of viral loads. Importantly, the efficacy of B cell therapy was partly dependent on antibody effector functions, and was improved by co-transferring virus-specific CD4 T cells. These findings provide a proof-of-concept that adoptive B cell therapy can be effective for the treatment of chronic infections, but provision of virus-specific CD4 T cells may be critical for optimal virus neutralization.

The impact of breast cancer on social cognition in female Colombian patients.

BACKGROUND: The high prevalence of female breast cancer is a global health concern. Breast cancer and its treatments have been associated with impairments in general cognition, as well as structural and functional brain changes. Considering the social challenges that some of these patients face, it is important to understand the socio-emotional effects of breast cancer as well. Nevertheless, the impact of breast cancer on social cognition has remained underexplored. The objective of this study was to assess social cognition domains and other relevant cognitive and emotional variables (executive functions, anxiety, or depression) in females with breast cancer. METHODS: The participants were 29 female patients diagnosed with breast cancer and 29 female healthy controls. We assessed emotion recognition, theory of mind, empathy, and moral emotions. We also included measures of general cognitive functioning, quality of life, anxiety, and depression. Linear multiple regressions were performed to assess whether the group (patients or controls), GAD-7 scores, emotional and social subscales of EORTC QLQ-C30, and IFS scores predicted the social cognition variables (EET, RMET, MSAT). RESULTS: Patients with breast cancer showed impairments in emotion recognition and in affective theory of mind. In addition, patients had lower scores in some executive functions. Only theory of mind between group differences remained significant after Bonferroni correction. Emotion recognition was associated with executive functioning, but anxiety levels were not a significant predictor of the changes in social cognition. CONCLUSIONS: Social cognition impairments, especially in theory of mind, may be present in breast cancer, which can be relevant to understanding the social challenges that these patients encounter. This could indicate the need for therapeutic interventions to preserve social cognition skills in patients with breast cancer.

T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID.

Many people experiencing long COVID syndrome, or post-acute sequelae of SARS-CoV-2 infection (PASC), suffer from debilitating neurologic symptoms (Neuro-PASC). However, whether virus-specific adaptive immunity is affected in Neuro-PASC patients remains poorly understood. We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated humoral and cellular responses toward SARS-CoV-2 Nucleocapsid protein at an average of 6 months post-infection compared to healthy COVID convalescents. Neuro-PASC patients also had enhanced virus-specific production of IL-6 from and diminished activation of CD8+ T cells. Furthermore, the severity of cognitive deficits or quality of life disturbances in Neuro-PASC patients were associated with a reduced diversity of effector molecule expression in T cells but elevated IFN-γ production to the C-terminal domain of Nucleocapsid protein. Proteomics analysis showed enhanced plasma immunoregulatory proteins and reduced pro-inflammatory and antiviral response proteins in Neuro-PASC patients compared with healthy COVID convalescents, which were also correlated with worse neurocognitive dysfunction. These data provide new insight into the pathogenesis of long COVID syndrome and a framework for the rational design of predictive biomarkers and therapeutic interventions.

Fractionating a COVID-19 Ad5-vectored vaccine improves virus-specific immunity.

SARS-CoV-2 has caused a global pandemic that has infected more than 250 million people worldwide. Although several vaccine candidates have received emergency use authorization, there is still limited knowledge on how vaccine dosing affects immune responses. We performed mechanistic studies in mice to understand how the priming dose of an adenovirus-based SARS-CoV-2 vaccine affects long-term immunity to SARS-CoV-2. We first primed C57BL/6 mice with an adenovirus serotype 5 vaccine encoding the SARS-CoV-2 spike protein, similar to that used in the CanSino and Sputnik V vaccines. The vaccine prime was administered at either a standard dose or 1000-fold lower dose, followed by a boost with the standard dose 4 weeks later. Initially, the low dose prime induced lower immune responses relative to the standard dose prime. However, the low dose prime elicited immune responses that were qualitatively superior and, upon boosting, exhibited substantially more potent recall and functional capacity. We also report similar effects with a simian immunodeficiency virus (SIV) vaccine. These findings show an unexpected advantage of fractionating vaccine prime doses, warranting a reevaluation of vaccine trial protocols for SARS-CoV-2 and other pathogens.

Limiting the priming dose of a SARS CoV-2 vaccine improves virus-specific immunity.

Since late 2019, SARS-CoV-2 has caused a global pandemic that has infected 128 million people worldwide. Although several vaccine candidates have received emergency use authorization (EUA), there are still a limited number of vaccine doses available. To increase the number of vaccinated individuals, there are ongoing discussions about administering partial vaccine doses, but there is still a paucity of data on how vaccine fractionation affects vaccine-elicited immunity. We performed studies in mice to understand how the priming dose of a SARS CoV-2 vaccine affects long-term immunity to SARS CoV-2. We first primed C57BL/6 mice with an adenovirus-based vaccine encoding SARS CoV-2 spike protein (Ad5-SARS-2 spike), similar to that used in the CanSino and Sputnik V vaccines. This prime was administered either at a low dose (LD) of 10 6 PFU or at a standard dose (SD) of 10 9 PFU, followed by a SD boost in all mice four weeks later. As expected, the LD prime induced lower immune responses relative to the SD prime. However, the LD prime elicited immune responses that were qualitatively superior, and upon boosting, mice that were initially primed with a LD exhibited significantly more potent immune responses. Overall, these data demonstrate that limiting the priming dose of a SARS CoV-2 vaccine may confer unexpected benefits. These findings may be useful for improving vaccine availability and for rational vaccine design.

Combining spike- and nucleocapsid-based vaccines improves distal control of SARS-CoV-2.

SARS-CoV-2 infection causes respiratory insufficiency and neurological manifestations, including loss of smell and psychiatric disorders, and can be fatal. Most vaccines are based on the spike antigen alone, and although they have shown efficacy at preventing severe disease and death, they do not always confer sterilizing immunity. Here, we interrogate whether SARS-CoV-2 vaccines could be improved by incorporating nucleocapsid as an antigen. We show that, after 72 h of challenge, a spike-based vaccine confers acute protection in the lung, but not in the brain. However, combining a spike-based vaccine with a nucleocapsid-based vaccine confers acute protection in both the lung and brain. These findings suggest that nucleocapsid-specific immunity can improve the distal control of SARS-CoV-2, warranting the inclusion of nucleocapsid in next-generation COVID-19 vaccines.

Cross-protective immunity following coronavirus vaccination and coronavirus infection.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicited cross-protective immune responses against heterologous coronaviruses. In particular, we show that a severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1 conferred robust heterologous protection against SARS-CoV-2 in mice. Similarly, prior coronavirus infections conferred heterologous protection against distinct coronaviruses. Cross-reactive immunity was also reported in patients with coronavirus disease 2019 (COVID-19) and in individuals who received SARS-CoV-2 vaccines, and transfer of plasma from these individuals into mice improved protection against coronavirus challenges. These findings provide the first demonstration to our knowledge that coronavirus vaccines (and prior coronavirus infections) can confer broad protection against heterologous coronaviruses and establish a rationale for universal coronavirus vaccines.

Interrogating Adaptive Immunity Using LCMV.

In this invited article, we explain technical aspects of the lymphocytic choriomeningitis virus (LCMV) system, providing an update of a prior contribution by Matthias von Herrath and J. Lindsay Whitton. We provide an explanation of the LCMV infection models, highlighting the importance of selecting an appropriate route and viral strain. We also describe how to quantify virus-specific immune responses, followed by an explanation of useful transgenic systems. Specifically, our article will focus on the following protocols. © 2020 Wiley Periodicals LLC. Basic Protocol 1: LCMV infection routes in mice Support Protocol 1: Preparation of LCMV stocks ASSAYS TO MEASURE LCMV TITERS Support Protocol 2: Plaque assay Support Protocol 3: Immunofluorescence focus assay (IFA) to measure LCMV titer MEASUREMENT OF T CELL AND B CELL RESPONSES TO LCMV INFECTION Basic Protocol 2: Triple tetramer staining for detection of LCMV-specific CD8 T cells Basic Protocol 3: Intracellular cytokine staining (ICS) for detection of LCMV-specific T cells Basic Protocol 4: Enumeration of direct ex vivo LCMV-specific antibody-secreting cells (ASC) Basic Protocol 5: Limiting dilution assay (LDA) for detection of LCMV-specific memory B cells Basic Protocol 6: ELISA for quantification of LCMV-specific IgG antibody Support Protocol 4: Preparation of splenic lymphocytes Support Protocol 5: Making BHK21-LCMV lysate Basic Protocol 7: Challenge models TRANSGENIC MODELS Basic Protocol 8: Transfer of P14 cells to interrogate the role of IFN-I on CD8 T cell responses Basic Protocol 9: Comparing the expansion of naïve versus memory CD4 T cells following chronic viral challenge.

Early type I IFN blockade improves the efficacy of viral vaccines.

Type I interferons (IFN-I) are a major antiviral defense and are critical for the activation of the adaptive immune system. However, early viral clearance by IFN-I could limit antigen availability, which could in turn impinge upon the priming of the adaptive immune system. In this study, we hypothesized that transient IFN-I blockade could increase antigen presentation after acute viral infection. To test this hypothesis, we infected mice with viruses coadministered with a single dose of IFN-I receptor-blocking antibody to induce a short-term blockade of the IFN-I pathway. This resulted in a transient "spike" in antigen levels, followed by rapid antigen clearance. Interestingly, short-term IFN-I blockade after coronavirus, flavivirus, rhabdovirus, or arenavirus infection induced a long-lasting enhancement of immunological memory that conferred improved protection upon subsequent reinfections. Short-term IFN-I blockade also improved the efficacy of viral vaccines. These findings demonstrate a novel mechanism by which IFN-I regulate immunological memory and provide insights for rational vaccine design.

A systematic review of brain functional connectivity patterns involved in episodic and semantic memory.

The study of functional connectivity and declarative memory has lately been focused on finding biomarkers of neuropsychological diseases. However, little is known about its patterns in healthy brains. Thus, in this systematic review we analyze and integrate the findings of 81 publications regarding functional connectivity (measured by fMRI during both task and resting-state) and semantic and episodic memory in healthy adults. Moreover, we discriminate and analyze the main areas and links found in specific memory phases (encoding, storage or retrieval) based on several criteria, such as time length, depth of processing, rewarding value of the information, vividness and amount or kind of details retrieved. There is a certain degree of overlap between the networks of episodic and semantic memory and between the encoding and retrieval stages. Although several differences are pointed out during the article, this calls to attention the need for further empirical studies that actively compare both types of memory, particularly using other baseline conditions apart from the traditional resting state. Indeed, the active involvement of the default mode network in both declarative memory and resting condition suggests the possibility that during rest there is an on-going memory processing. We find support for the 'attention to memory' hypothesis, the memory differentiation model and the appropriate transfer hypothesis, but some evidence is inconsistent with the traditional hub-and-spoke model.