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bioRxiv2022

Uman Type NF-L Antibodies Are Effective Reagents for the Imaging of Neurodegeneration

Recent work shows that certain immunological assays for the neurofilament light chain NF-L detect informative signals in the CSF and blood of human and animals affected by a variety of CNS injury and disease states. Much of this work has been performed using two mouse monoclonal antibodies to NF-L, UD1 and UD2, also known as 2.1 and 47.3 respectively. These are the essential components of the Uman Diagnostics NF-Light ELISA kit, the Quanterix Simoa bead based NF-L assay and others. We show here that the antibodies bind to neighboring epitopes in a short, conserved and unusual peptide in the NF-L "rod" Coil 2 region. We also describe a surprising and useful feature of Uman and similar reagents. While other well characterized NF-L antibodies show robust staining of countless cells and processes in CNS sections from healthy rats, both Uman antibodies reveal only a minor subset of presumably spontaneously degenerating or degenerated neurons and their processes. However following experimental mid-cervical injuries to rat spinal cord both Uman antibodies recognize numerous profiles in tissue sections. The Uman positive material was associated with fiber tracts expected to be damaged by the injury administered and the profiles had the swollen, beaded, discontinuous and sinusoidal morphology expected for degenerating and degenerated processes. We also found that several antibodies to the C terminal "tail" region of NF-L stain undamaged axonal profiles but fail to recognize the Uman positive material. The unmasking of the Uman epitopes and the loss of the NF-L tail epitopes can be mimicked by treating sections from healthy animals with proteases suggesting that the immunological changes we have discovered are due to neurodegeneration induced proteolysis. We have also generated a novel panel of monoclonal and polyclonal antibody reagents directed against the region of NF-L including the Uman epitopes which have staining properties identical to the Uman reagents. Using these we show that the NF-L region to which the Uman reagents bind contains further hidden epitopes distinct from those recognized by the two Uman reagents. We speculate that the Uman type epitopes are part of a binding region important for higher order neurofilament assembly. The work provides important insights into the properties of the NF-L biomarker, describes novel and useful properties of Uman type and NF-L tail binding antibodies and provides a hypothesis relevant to further understanding of neurofilament assembly.

neuroscience↗

bioRxiv2022

ROCKETS - a novel one-for-all toolbox for light sheet microscopy in drug discovery

Advancing novel immunotherapy strategies requires refined tools in preclinical research to thoroughly assess drug targets, biodistribution, safety, and efficacy. Light sheet fluorescence microscopy (LSFM) offers unprecedented fast volumetric ex vivo imaging of large tissue samples in high resolution. Yet, to date laborious and unstandardized tissue processing procedures have limited throughput and broader applications in immunological research. Therefore, we have developed a simple and harmonized protocol for processing, clearing and imaging of all mouse organs and even entire mouse bodies. Applying this Rapid Optical Clearing Kit for Enhanced Tissue Scanning (ROCKETS) in combination with LSFM allowed us to comprehensively study the in vivo biodistribution of an antibody targeting Epithelial Cell Adhesion Molecule (EpCAM) in 3D. Quantitative high-resolution scans of whole organs did not only reveal known EpCAM expression patterns but, importantly, uncovered several new EpCAM-binding sites. We identified choroid plexi in the brain and duodenal papillae as unexpected locations of high EpCAM-expression. These tissue locations may be considered as particularly sensitive sites due their importance for liquor production or as critical junctions draining bile and digestive pancreatic enzymes into the small bowel, respectively. These newly gained insights appear highly relevant for clinical translation of EpCAM-addressing immunotherapies. Thus, ROCKETS in combination with LSFM may help to set new standards for preclinical evaluation of immunotherapeutic strategies. Conclusively, we propose ROCKETS as an ideal platform for a broader application of LSFM in immunological research optimally suited for quantitative co-localization studies of immunotherapeutic drugs and defined cell populations in the microanatomical context of organs or even whole mice.

pharmacology and toxicology↗

bioRxiv2022

Differential innate immune response of endometrial cells to porcine reproductive and respiratory syndrome virus type 1 versus type 2

Modification of cellular and immunological events due to porcine reproductive and respiratory syndrome virus (PRRSV) infection is associated with pathogenesis in lungs. PRRSV also causes female reproductive dysfunction and persistent infection which can spread to fetus, stillbirth, and offspring. In this study, alterations in cellular and innate immune responses to PRRSV type 1 or type 2 infection, including expression of PRRSV mediators, mRNA expression of toll-like receptor (TLRs) and cytokine, and cytokine secretion, were examined in primary porcine glandular endometrial cells (PGE). Cell infectivity as observed by cytopathic effect (CPE), PRRSV nucleocapsid proteins, and viral nucleic acids was early detected at two days post-infection (2 dpi) and persisted to 6 dpi. Higher percentage of CPE and PRRSV positive cells were detected in type 2 infection. PRRSV mediator proteins, CD151, CD163, sialoadhesin (Sn), integrin and vimentin, were upregulated following type 1 and type 2 infection. CD151, CD163 and Sn were upregulated by type 2. Both PRRSV types upregulated TLR1 and TLR6. Only type 2 infection upregulated TLR3, but downregulated TLR4 and TLR8. By contrast, both types upregulated TLR4 and downregulated TLR6 protein expression. Interleukin (IL)-1{beta}, IL-6 and tumor necrotic factor (TNF)- were upregulated by type 2, but IL-8 was upregulated by type 1. Both PRRSV type 1 and 2 stimulated IL-6 but suppressed TNF- secretion. In addition, IL-1{beta} secretion was suppressed by type 2. These findings reveal one of the important mechanisms underlying the strategy of PRRSV on innate immune evasion in endometrium which is associated with the viral persistence. Author SummaryWidely prevalence of porcine reproductive and respiratory syndrome virus (PRRSV) remains the leading cause of huge economic losses to the global swine industry. Due to an infection of macrophages, PRRSV can persist in animals for extended periods of time associated with long-lasting reproductive disorders. Modification of cellular and immunological responses to PRRSV infection which may be related with the pathogenesis of reproductive disorders remains unclear. Herein, direct PRRSV infection of primary porcine glandular endometrial epithelial cell culture (PGE) demonstrated that PRRSV type 1 and 2 upregulated the protein expression of PRRSV mediators correlated with cell persistence of PRRSV. However, TLR and cytokines gene expression, and cytokine secretion were differentially modulated in response to PRRSV type 1 vs. type 2. Our study provides new insights into the cellular mechanism associating with PRRSV persistence in the endometrial cells and the underlying interaction of virus with the host.

microbiology↗

bioRxiv2022

Discovery of tumor resident oncolytic bacteria toward targeted anticancer theranostics

Unveiling the different biomedical functions of tumor-resident microbiota has remained challenging for the development of advanced anticancer medicines. Here we show that isolated intratumoral bacteria with its association with natural purple photosynthetic bacteria have a high innate biocompatibility and drastic immunogenic anticancer efficacies. They preferentially grow and proliferate within targeted tumor milieu, which effectively causes immune cells to infiltrate the tumor and provoke strong anticancer responses in various syngeneic mouse models including those of colorectal cancer, sarcoma, metastatic lung cancer, and extensive drug-resistant breast cancer. Furthermore, these functional bacteria-treated mice, that exhibit excellent anticancerous responses of tumors, have significantly prolonged survival rates with effective immunological memory. Notably, light-harvesting nanocomplexes of microbial consortium of intratumoral bacteria and purple photosynthetic bacteria is capable of tumor diagnosis using bio-optical-window near-infrared light, making them useful theranostic agents for highly targeted immunological elimination of the tumor and for precisely marking tumor location.

bioengineering↗

bioRxiv2022

SARS-CoV-2 variant transition dynamics are associated with vaccination rates, number of co-circulating variants, and natural immunity

BackgroundThroughout the COVID-19 pandemic, the SARS-CoV-2 virus has continued to evolve, with new variants outcompeting existing variants and often leading to different dynamics of disease spread. MethodsIn this paper, we performed a retrospective analysis using longitudinal sequencing data to characterize differences in the speed, calendar timing, and magnitude of 13 SARS-CoV-2 variant waves/transitions for 215 countries and sub-country regions, between October 2020 and October 2022. We then clustered geographic locations in terms of their variant behavior across all Omicron variants, allowing us to identify groups of locations exhibiting similar variant transitions. Finally, we explored relationships between heterogeneity in these variant waves and time-varying factors, including vaccination status of the population, governmental policy, and the number of variants in simultaneous competition. FindingsThis work demonstrates associations between the behavior of an emerging variant and the number of co-circulating variants as well as the demographic context of the population. We also observed an association between high vaccination rates and variant transition dynamics prior to the Mu and Delta variant transitions. InterpretationThese results suggest the behavior of an emergent variant may be sensitive to the immunologic and demographic context of its location. Additionally, this work represents the most comprehensive characterization of variant transitions globally to date. FundingLaboratory Directed Research and Development (LDRD), Los Alamos National Laboratory Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSARS-CoV-2 variants with a selective advantage are continuing to emerge, resulting in variant transitions that can give rise to new waves in global COVID-19 cases and changing dynamics of disease spread. While variant transitions have been well studied individually, more work is needed to better understand how variant transitions have occurred in the past and how properties of these transitions may relate to vaccination rates, natural immunity, and population demographics. Added value of this studyOur retrospective study integrates metadata based on 12.8 million SARS-CoV-2 sequences available through the Global Initiative on Sharing All Influenza Data (GISAID) with clinical and demographic data to characterize heterogeneity in variant waves/transitions across the globe throughout the COVID-19 pandemic. We demonstrate that properties of the variant transitions (e.g., speed, timing, and magnitude of the transition) are associated with vaccination rates, prior COVID-19 cases, and the number of co-circulating variants in competition. Implications of all the available evidenceOur results indicate that there is substantial heterogeneity in how an emerging variant may compete with other viral variants across locations, and suggest that each locations contemporaneous immunologic landscape may play a role in these interactions.

bioinformatics↗

bioRxiv2022

A simple within-host, between-host model for a vector-transmitted disease

We present a model that explicitly links the epidemiological Ross-Macdonald model with a simple immunological model through a virus inoculation term that depends on the abundance of infected mosquitoes. We explore the relationship between the reproductive numbers at the population (between-host) and individual level (within-host), in particular the role that viral load and viral clearance rate play in the coupled dynamics. Our model shows that under certain conditions on the strength of the coupling and the immunological response of the host, there can be sustained low viral load infections, with a within-host reproduction number below one that still can trigger epidemic outbreaks provided the between host reproduction number is greater than one. We also describe a particular kind of transmission-clearance trade off for vector-host systems with a simple structure.

systems biology↗

bioRxiv2022

Pre-clinical in vitro and in vivo characterization of a maternal vaccination before conception to protect against severe neonatal infections caused by Escherichia coli K1

Preterm birth remains the leading cause of neonatal morbidity and mortality today. Genetic, immunological, and infectious substrates are suspected. Preterm infants are at higher risk of severe neonatal infections and the main cause of bacterial infection in this population is Escherichia coli K1. Unfortunately, women with history of preterm birth have a high risk of recurrence. Therefore, these women constitute a target population for a vaccine, to date non-existent, against E. coli K1 to prevent these infections. In this study, we characterize the immunological and microbiological properties in adult female mice of a live attenuated vaccine candidate and the protection it conferred to newborn mice against severe infection caused by E. coli K1. We show that our E. coli K1 {Delta}aroA vaccine induces a strong immunity driven by polyclonal bactericidal antibodies. In our model of meningitis, pups born from mothers immunized before conception were strongly protected against different strains of E. coli K1 both in early-onset and late-onset diseases. Given the very high rate of mortality and neurological sequalae in neonatal meningitis caused by E. coli K1, this pre-clinical study provides a proof-of-concept for the development of a vaccine strategy against E. coli K1 severe infection in women at risk of preterm birth.

microbiology↗

bioRxiv2023

Urban living can rescue Darwin's finches from the lethal effects of invasive vampire flies

Human activity changes multiple factors in the environment, which can have additive or neutralizing effects on organisms. However, few studies have explored the causal effects of multiple anthropogenic factors, such as urbanization and invasive species, on animals, and the mechanisms that mediate these interactions. This study examines the influence of urbanization on the detrimental effect of invasive avian vampire flies (Philornis downsi) on endemic Darwins finches in the Galapagos Islands. We experimentally manipulated nest fly abundance in an urban and non-urban area and then characterized nestling health, survival, diet, and gene expression patterns related to host defense. Survival of fumigated nestlings from urban and non-urban nests did not differ significantly. However, sham-fumigated, non-urban nestlings lost more blood and few nestlings survived compared to urban nestlings. Stable isotopic values ({delta}15N) from urban nestling feces were higher than non-urban nestlings, suggesting that urban nestlings are consuming more protein. {delta}15N values correlated negatively with parasite abundance, which suggests that diet might influence host defenses (e.g., tolerance and resistance). Parasitized urban nestlings differentially expressed genes within pathways associated with red blood cell production (tolerance) and pro-inflammatory response (innate immunological resistance), compared to sham-fumigated non-urban nestlings. In contrast, sham-fumigated non-urban nestlings differentially expressed genes within pathways associated with immunoglobulin production (adaptive immunological resistance). Our results suggest that urban nestlings are investing more in pro-inflammatory responses to resist parasites, but also recovering more blood cells to tolerate blood loss. Although non-urban nestlings are mounting an adaptive immune response, it is likely a last effort by the immune system rather than an effective defense against avian vampire flies since few nestlings survived.

ecology↗

bioRxiv2023

Immune clustering reveals molecularly distinct subtypes of lung adenocarcinoma

Lung adenocarcinoma, the most prevalent type of non-small cell lung cancer, consists of two driver mutations in KRAS or EGFR. In general, these mutations are mutually exclusive, and biologically and clinically different. In this study, we attempted to find if we could separate lung adenocarcinoma tumors by their immune profile using an unsupervised machine learning method. By projecting RNA-seq data into inferred immune profiles and using unsupervised learning, we were able to divide the lung adenocarcinoma population into three subgroups, one of which appeared to contain mostly EGFR patients. We argue that EGFR mutations in each subgroup are different immunologically which implies a distinct tumor microenvironment and might relate to the relatively high resistance of EGFR-positive tumors to immune checkpoint inhibitors. However, we could not make the same claim about KRAS mutations. Simple SummaryLung adenocarcinoma, the most prevalent type of non-small cell lung cancer, is most commonly driven by mutations in KRAS or EGFR. In this study, we attempted to find if we could separate lung adenocarcinoma tumors by their immune profile using an unsupervised machine learning method. We used established tools to infer the immune profile of each tumor from its RNA-seq and using unsupervised learning, we were able to divide the lung adenocarcinoma population into three subgroups, one of which appeared to contain mostly patients with EGFR mutations. We argue that tumors with EGFR mutations in each subgroup are different immunologically which implies a distinct tumor microenvironment and might relate to the relatively high resistance of EGFR-positive tumors to immune checkpoint inhibitors. However, we could not make the same claim about KRAS mutations.

cancer biology↗

bioRxiv2023

Multiple myeloma long-term survivors display sustained immune alterations decades after first line therapy

The long-term consequences of cancer or cancer therapy on the patients immune system years after cancer-free survival remain poorly understood. Here, we have performed an in-depth characterization of the bone marrow ecosystem of multiple myeloma long-term survivors at initial diagnosis and up to 17 years following cancer-free survival. Using comparative single-cell analyses in combination with molecular, genomic and functional approaches, we demonstrate that multiple myeloma long-term survivors display pronounced alterations in their bone marrow microenvironment associated with impaired immunity. These immunological alterations were frequently driven by an inflammatory immune circuit fueled by the long-term persistence or resurgence of residual myeloma cells. Notably, even in the complete absence of any detectable residual disease for decades, sustained changes in the immune system were observed, suggesting an irreversible immunological scarring caused by the initial exposure to the cancer and therapy. Collectively, our study provides key insights into the molecular and cellular bone marrow ecosystem of multiple myeloma long-term survivors, revealing reversible and irreversible alterations of the immune compartment, which can serve as diagnostic and predictive tools. Statement of significanceLarge-scale single-cell profiling of a unique cohort of multiple myeloma long-term survivors uncovered that exposure to cancer and its treatment causes both reversible and irreversible immune alterations associated with impaired immunity. These findings have far-reaching implications for the understanding of long-term immune alterations in cancer, which need to be considered also in the context of immune therapeutic approaches. Furthermore, our study demonstrates how cancer-associated immune trafficking can be used to predict disease re-initiation in the bone marrow, opening new avenues for minimally invasive disease monitoring.

cancer biology↗

bioRxiv2023

Binary Ethyleneimine inactivated- Encephalomyocarditis virus as an experimental vaccine candidate showed strong neutralization responses.

A novel Encephalomyocarditis virus (EMCV) of the group 3 cluster (EMCV-3) was first reported in 2002 to be responsible for the deaths of orang-utans in an outbreak in the Singapore Zoo. After this first outbreak, sporadic infections among the primate population caused by EMCV-3 continued to be reported, suggesting that the virus remains prevalent in Singapore. To prevent future infections, we constructed an experimental vaccine using binary ethylenimine (BE) to inactivate the EMCV-3 virus. The immunological performance of the BE-inactivated (BEI) virus was analysed in mice and the neutralising titre of the immune sera measured against the wild-type EMCV-3. The BEI virus showed a strong immunological response in BALB/c mice at 1: 40,960 titre, suggesting that it can be used as a promising experimental vaccine candidate to prevent EMCV-3 infections.

microbiology↗

bioRxiv2023

SARS-CoV-2 Neutralizing Antibodies Following a Second BA.5 Bivalent Booster

Bivalent COVID-19 mRNA vaccines expressing both the ancestral D614G and Omicron BA.5 spike proteins were introduced in August 2022 with the goal of broadening immunity to emerging SARS-CoV-2 Omicron subvariants. Subsequent studies on bivalent boosters found neutralizing antibody responses similar to boosters with the original monovalent vaccine, likely the result of immunological imprinting. Guidelines allow for administration of a second bivalent booster in high-risk groups, but it remains unknown whether this would broaden antibody responses. To address this question, we assessed longitudinal serum SARS-CoV-2-neutralizing titers in 18 elderly immunocompetent individuals (mean age 69) following a fourth monovalent booster and two BA.5 bivalent booster vaccines using pseudovirus neutralization assays against D614G, Omicron BA.5, and Omicron XBB.1.5. There was a small but significant increase in peak neutralizing antibody responses against Omicron BA.5 and XBB.1.5 following the first bivalent booster, but no significant increase in peak titers following the second bivalent booster. Omicron-specific neutralizing titers remained low after both doses of the BA.5 bivalent booster. Our results suggest that a second dose of the BA.5 bivalent booster is not sufficient to broaden antibody responses and to overcome immunological imprinting. A monovalent vaccine targeting only the spike of the recently dominant SARS-CoV-2 may mitigate the "back boosting" associated with the "original antigenic sin."

microbiology↗

bioRxiv2023

Enhanced functionalities of immune cells separated by microfludic lattice: assessment based on holotomography

The isolation of white blood cells (WBCs) from whole blood constitutes a pivotal process for immunological studies, diagnosis of hematologic disorders, and the facilitation of immunotherapy. Despite the ubiquity of density gradient centrifugation in WBC isolation, its influence on WBC functionality remains inadequately understood. This research employs holotomography to explore the effects of two distinct WBC separation techniques, namely conventional centrifugation and microfluidic separation, on the functionality of the isolated cells. We utilize three-dimensional refractive index distribution and time-lapse dynamics to conduct an in-depth analysis of individual WBCs, focusing on their morphology, motility, and phagocytic capabilities. Our observations highlight that centrifugal processes negatively impacts WBC motility and phagocytic capacity, whereas microfluidic separation yields a more favorable outcome in preserving WBC functionality. These findings emphasize the potential of microfluidic separation techniques as a viable alternative to traditional centrifugation for WBC isolation, potentially enabling more precise analyses in immunology research and improving the accuracy of hematologic disorder diagnoses.

biophysics↗

bioRxiv2023

STING activation counters glioblastoma by vascular alteration and immune surveillance

Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New immunotherapy approaches and a deeper understanding of immune surveillance of GBM are needed to advance treatment options for this devastating disease. In this study, we used two preclinical models of GBM: orthotopically delivering either GBM stem cells or employing CRISPR-mediated tumorigenesis by adeno-associated virus, to establish immunologically proficient and non-inflamed tumors, respectively. After tumor development, the innate immune system was activated through long-term STING activation by a pharmacological agonist, which reduced tumor progression and prolonged survival. Recruitment and activation of cytotoxic T-cells were detected in the tumors, and T-cell specificity towards the cancer cells was observed. Interestingly, prolonged STING activation altered the tumor vasculature, inducing hypoxia and activation of VEGFR, as measured by a kinome array and VEGF expression. Combination treatment with anti-PD1 did not provide a synergistic effect, indicating that STING activation alone is sufficient to activate immune surveillance and hinder tumor development through vascular disruption. These results guide future studies to refine innate immune activation as a treatment approach for GBM, in combination with anti-VEGF to impede tumor progression and induce an immunological response against the tumor.

cancer biology↗

bioRxiv2023

An Immuno-Epidemiological Model of Foot-and-Mouth Disease (FMD) in the African Buffalo Population with Carrier Transmission

Foot-and-mouth disease (FMD) is a highly contagious disease that spreads among cloven-hoofed animals. Although not deadly, FMD can cause major delays in meat and dairy production. One major concern is that the foot-and-mouth disease virus (FMDV) can persist in African buffalo hosts as natural reservoirs for long periods of time, causing the pathogens to reemerge in susceptible populations. In this paper, we present a novel immuno-epidemiological model of FMD in the African buffalo host populations. Upon infection, the hosts can undergo two phases, namely the acute and the carrier stages. In our model, we divide the infectious population based upon these two stages so that we can dynamically capture the immunological characteristics of both phases of the disease to better understand the carriers role in disease transmission. We first define the within-host viral-immune kinetics dependent epidemiological basic reproduction number[R] 0 and show that it is a threshold condition for the local stability of the disease-free equilibrium and existence of the endemic equilibrium. We also analytically show that the system always displays forward bifurcation with respect to between-host epidemic parameters. Later, by using a sensitivity analysis (SA) approach developed for multi-scale models, we assess the impact of the acute infection and carrier phase immunological parameters on[R] 0. Interestingly, our numerical results show that the within-carrier infected host immune kinetics parameters and the susceptible individual recruitment rates play significant roles in disease persistence, which are consistent with experimental and field studies.

systems biology↗

bioRxiv2023

Alteration of mechanical stresses in the murine brain by age and hemorrhagic stroke

Residual mechanical stresses in tissues arise during rapid differential growth or remodeling such as in morphogenesis and cancer. These residual stresses, also known as solid stresses, are distinct from fluid pressures and dissipate in most healthy adult organs as the rate of growth decreases. However, studies have shown that residual stresses remain substantially high even in mature, healthy brains. The genesis and consequences of these mechanical stresses in a healthy brain, and in aging and disease remain to be explored. Here, we utilized and validated our previously developed method to map residual mechanical stresses in the brains of mice in three different age groups: 5-7 days, 8-12 weeks, and 22 months old. We found that residual solid stress increases rapidly from 5-7 days to 8-12 weeks in mice, and remains high even in mature 22-month-old mice brains. Three-dimensional mapping of the residual stresses revealed an increasing trend from anterior to posterior in coronal sections of the brain. Since the brain is rich in negatively charged hyaluronic acid, we evaluated the contribution of charged extracellular matrix (ECM) constituents in maintaining solid stress levels. We found that lower ionic strength leads to elevated solid stresses, a finding consistent with the unshielding effect of low ionic strength and the subsequent expansion of charged ECM components. Lastly, we demonstrated that hemorrhagic stroke, accompanied by loss of cellular density, resulted in decreased levels of residual stress in the murine brain. Our findings contribute to a better understanding of the spatiotemporal alteration of residual solid stresses in healthy and diseased brains, a crucial step toward uncovering the biological and immunological consequences of this understudied mechanical phenotype in the brain. Significance StatementWhile emerging evidence highlights the importance of solid stresses in embryogenesis and tumor growth, the genesis and consequences of residual solid stresses in the adult normal brain remain poorly understood. Understanding the spatiotemporal distribution and alteration of the residual solid stresses as the brain ages and is impacted by neuropathologies, such as a stroke, will elucidate the biological and immunological consequences of maintaining these stresses. This study suggests solid stress could serve as a potential biomarker in aging and diseases associated to the brain.

biophysics↗

bioRxiv2024

Modeling Combination Chemo-Immunotherapy for Heterogeneous Tumors

Hypermutable cancers create opportunities for the development of various immunotherapies, such as immune checkpoint blockade (ICB) therapy. However, emergent studies have revealed that many hypermutated tumors have poor prognosis due to heterogeneous tumor antigen landscapes, yet the underlying mechanisms remain poorly understood. To address this issue, we developed mathematical models to explore the impact of combining chemotherapy and ICB therapy on heterogeneous tumors. Our results uncover how chemotherapy reduces antigenic heterogeneity, creating improved immunological conditions within tumors, which, in turn, enhances the therapeutic effect when combined with ICB. Furthermore, our results show that the recovery of the immune system after chemotherapy is crucial for enhancing the response to chemo-ICB combination therapy. Author summaryThe challenge posed by intratumoral heterogeneity is gaining recognition in the field of cancer treatment. Despite the success of immune checkpoint blockade (ICB) therapies in enhancing overall survival across various cancer types, the complexity of therapeutic responses persists due to the heterogeneity of tumor antigens. In this study, we developed mathematical models to explore the evolutionary dynamics of tumors with both homogeneous and heterogeneous antigen landscapes. Our analysis reveals that tumors with heterogeneity exhibit resistance to ICB therapy, unlike their homogeneous counterparts which respond positively. Additionally, our models demonstrate that early treatment of heterogeneous tumors with chemotherapy leads to significant remission but also rapid recurrence. Notably, we identified a fascinating trade-off associated with chemotherapy--while suppressing the immune system, it creates a tumor immunological environment that becomes more conducive to ICB therapy. Finally, our modeling highlights the augmented response observed in tumors subjected to a chemo-ICB combination and shows the crucial role of immune recovery in the context of combination therapy.

evolutionary biology↗

bioRxiv2024

Contribution of parasite and host genotype to immunopathology of schistosome infections

BackgroundThe role of pathogen genotype in determining disease severity and immunopathology has been studied intensively in microbial pathogens including bacteria, fungi, protozoa, and viruses, but is poorly understood in parasitic helminths. The medically important blood fluke Schistosoma mansoni is an excellent model system to study the impact of helminth genetic variation on immunopathology. Our laboratory has demonstrated that laboratory schistosome populations differ in sporocyst growth and cercarial production in the intermediate snail host and worm establishment and fecundity in the vertebrate host. Here, we (i) investigate the hypothesis that schistosome genotype plays a significant role in immunopathology and related parasite life history traits in the vertebrate mouse host and (ii) quantify the relative impact of parasite and host genetics on infection outcomes. MethodsWe infected BALB/c and C57BL/6 mice with four different laboratory schistosome populations from Africa and the Americas. We quantified disease progression in the vertebrate host by measuring body weight and complete blood count (CBC) with differential over an infection period of 12 weeks. On sacrifice, we assessed parasitological (egg and worm counts, fecundity), immunopathological (organ measurements and histopathology), and immunological (CBC with differential and cytokine profiles) characteristics to determine the impact of parasite and host genetics. ResultsWe found significant variation between parasite populations in worm numbers, fecundity, liver and intestine egg counts, liver and spleen weight, and fibrotic area, but not in granuloma size. Variation in organ weight was explained by egg burden and by intrinsic parasite factors independent of egg burden. We found significant variation between infected mouse lines in cytokines (IFN-{gamma}, TNF-), eosinophil, lymphocyte, and monocyte counts. ConclusionsThis study showed that both parasite and host genotype impact the outcome of infection. While host genotype explains most of the variation in immunological traits, parasite genotype explains most of the variation in parasitological traits, and both host and parasite genotype impact immunopathology outcomes.

microbiology↗