Education & Certifications
Doctor of Philosophy, Johns Hopkins University (2021)
Bachelor of Science, University of Florida (2015)
Detection of SARS-CoV-2 Antibodies in Immunoglobulin Products.
The journal of allergy and clinical immunology. In practice
BACKGROUND: For patients with primary antibody deficiency, the first line of therapy is replacement with immunoglobulin (Ig) products. Prior to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, Ig products did not contain antibodies with specificity for this virus, and there have been limited data on the antibodies present in the Ig products in current use.OBJECTIVE: To quantitatively examine SARS-CoV-2 antibodies in current immunoglobulin products.METHODS: 142 unique lots of 11 different Ig products intended for intravenous (IV) and/or subcutaneous (SC) delivery were examined for IgG binding activities against recombinant SARS-CoV-2 receptor binding domain (RBD), spike, and nucleocapsid proteins (NP) by enzyme-linked immunosorbent assays (ELISA). Additionally, to assess functionality, 48 of these unique lots were assessed for their ability to inhibit the variants SARS-CoV-2 Ancestral, Alpha, Beta, Delta, and Omicron spike binding to angiotensin converting enzyme 2 (ACE2).RESULTS: Significantly increased antibody values were observed for products manufactured after the year 2020 (expiration dates 2023-2024), as compared to Ig products before 2020 (pre-pandemic). Sixty and eighty-five percent of the Ig products with expiration dates of 2023 and 2024 were positive for antibody to SARS-CoV-2 proteins, respectively. AUC values were significantly higher in products with later expiration dates. Later dates of expiration were also strongly correlated with inhibition of ACE2 binding activity, however a decline in inhibition activity was observed with later variants.CONCLUSION: Overall, more recent Ig products (expiration dates: 2023 - 2025) contained significantly higher binding and inhibition activities against SARS-CoV-2 proteins, as compared to earlier, or pre-pandemic products. Normal donor SARS-CoV-2 antibodies are capable of inhibiting ACE2-binding activities and may provide a therapeutic benefit for patients who do not make a robust vaccine response.
View details for DOI 10.1016/j.jaip.2023.05.005
View details for PubMedID 37182564
An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss.
2022; 13 (1): 6808
The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.
View details for DOI 10.1038/s41467-022-34617-7
View details for PubMedID 36357396
Localization of Salmonella and albumin-IL-2 to the tumor microenvironment augments anticancer T cell immunity.
Journal of biomedical science
2022; 29 (1): 57
BACKGROUND: For centuries, microbial-based agents have been investigated as a therapeutic modality for the treatment of cancer. In theory, these methods would be cheap to produce, broadly applicable in a wide array of cancer types, and could synergize with other cancer treatment strategies. We aimed to assess the efficacy of combining microbial-based therapy using Salmonella SL7207 with interleukin-2 (IL-2), a potent immunostimulatory agent, in the treatment of murine colon carcinoma.METHODS: Female BALB/c mice were implanted subcutaneously with CT26 tumors, a model of colon carcinoma. Mice bearing tumors were selected and administered Albumin-IL-2 (Alb-IL2), a fusion protein, for further analysis of anticancer effect.RESULTS: We demonstrated that Salmonella SL7207, a genetically modified strain of Salmonella enterica serovar Typhimurium, preferentially accumulates in the tumor microenvironment, potentiating it to stimulate localized innate immunity. We delivered IL-2 as a fusion protein, Alb-IL2, which we demonstrate to have preferential accumulation properties, bringing it to the tumor and secondary lymphoid organs. Treatment of tumor-bearing mice with Salmonella+Alb-IL2 leads to superior tumor control and enhanced overall survival compared to controls. When assessing immunological factors contributing to our observed tumor control, significantly enhanced T cell population with superior effector function was observed in mice treated with Salmonella+Alb-IL2. We confirmed that these T cells were indispensable to the observed tumor control through antibody-mediated T cell depletion experiments.CONCLUSIONS: These findings highlight the ability of Salmonella+Alb-IL2 to serve as a novel therapeutic approach to induce T cell-mediated antitumor immunity and exert long-term tumor control in a murine model of cancer.
View details for DOI 10.1186/s12929-022-00841-y
View details for PubMedID 35962391
Albumin and interferon-beta fusion protein serves as an effective vaccine adjuvant to enhance antigen-specific CD8+ T cell-mediated antitumor immunity.
Journal for immunotherapy of cancer
2022; 10 (4)
BACKGROUND: Type I interferons (IFN) promote dendritic cells maturation and subsequently enhance generation of antigen-specific CD8 +T cell for the control of tumor. Using type I interferons as an adjuvant to vaccination could prove to be a potent strategy. However, type I interferons have a short half-life. Albumin linked to a protein will prolong the half-life of the linked protein.METHODS: In this study, we explored the fusion of albumin to IFNbeta (Alb-IFNbeta) for its functional activity both in vitro and in vivo. We determined the half-life of Alb-IFNbeta following treatment in the serum, tumor, and tumor draining lymph nodes in both wild type and FcRn knockout mice. We characterized the ability of Alb-IFNbeta to enhance antigen-specific CD8+ T cells using ovalbumin (OVA) or human papillomavirus (HPV) E7 long peptides. Next, we evaluated the therapeutic antitumor effect of coadministration of AlbIFNbeta with antigenic peptides against HPVE7 expressing tumor and the treatment's ability to generate HPVE7 antigen specific CD8+ T cells. The contribution of the antitumor effect by lymphocytes was also examined by an antibody depletion experiment. The ability of Alb-IFNbeta to serve as an adjuvant was tested using clinical grade therapeutic protein-based HPV vaccine, TACIN.RESULTS: Alb-IFNbeta retains biological function and does not alter the biological activity of IFNbeta. In addition, Alb-IFNbeta extends half-life of IFNbeta in serum, lymph nodes and tumor. The coadministration of Alb-IFNbeta with OVA or HPVE7 antigenic peptides enhances antigen-specific CD8 +T cell immunity, and in a TC-1 tumor model results in a significant therapeutic antitumor effect. We found that CD8 +T cells and dendritic cells, but not CD4 +T cells, are important for the observed antitumor therapeutic effect mediated by Alb-IFNbeta. Finally, Alb-IFNbeta served as a potent adjuvant for TA-CIN for the treatment of HPV antigen expressing tumors.CONCLUSIONS: Overall, Alb-IFNbeta serves as a potent adjuvant for enhancement of strong antigen-specific CD8 +T cell antitumor immunity, reduction of tumor burden, and increase in overall survival. Alb-IFNbeta potentially can serve as an innovative adjuvant for the development of vaccines for the control of infectious disease and cancer.
View details for DOI 10.1136/jitc-2021-004342
View details for PubMedID 35459734
Repeatability and reproducibility of a handheld quantitative G6PD diagnostic.
PLoS neglected tropical diseases
2022; 16 (2): e0010174
The introduction of novel short course treatment regimens for the radical cure of Plasmodium vivax requires reliable point-of-care diagnosis that can identify glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. While deficient males can be identified using a qualitative diagnostic test, the genetic make-up of females requires a quantitative measurement. SD Biosensor (Republic of Korea) has developed a handheld quantitative G6PD diagnostic (STANDARD G6PD test), that has approximately 90% accuracy in field studies for identifying individuals with intermediate or severe deficiency. The device can only be considered for routine care if precision of the assay is high.Commercial lyophilised controls (ACS Analytics, USA) with high, intermediate, and low G6PD activities were assessed 20 times on 10 Biosensor devices and compared to spectrophotometry (Pointe Scientific, USA). Each device was then dispatched to one of 10 different laboratories with a standard set of the controls. Each control was tested 40 times at each laboratory by a single user and compared to spectrophotometry results. When tested at one site, the mean coefficient of variation (CV) was 0.111, 0.172 and 0.260 for high, intermediate, and low controls across all devices respectively; combined G6PD Biosensor readings correlated well with spectrophotometry (rs = 0.859, p<0.001). When tested in different laboratories, correlation was lower (rs = 0.604, p<0.001) and G6PD activity determined by Biosensor for the low and intermediate controls overlapped. The use of lyophilised human blood samples rather than fresh blood may have affected these findings. Biosensor G6PD readings between sites did not differ significantly (p = 0.436), whereas spectrophotometry readings differed markedly between sites (p<0.001).Repeatability and inter-laboratory reproducibility of the Biosensor were good; though the device did not reliably discriminate between intermediate and low G6PD activities of the lyophilized specimens. Clinical studies are now required to assess the devices performance in practice.
View details for DOI 10.1371/journal.pntd.0010174
View details for PubMedID 35176015
THE STANDARD G6PD TEST (SD BIOSENSOR) SHOWS GOOD REPEATABILITY AND REPRODUCIBILITY IN A MULTI-LABORATORY COMPARISON
AMER SOC TROP MED & HYGIENE. 2021: 346
View details for Web of Science ID 000778105603175
SOCS1 mimetics attenuate autoimmune pathology in a murine model of lupus
AMER ASSOC IMMUNOLOGISTS. 2021
View details for Web of Science ID 000713665801092
Novel immunotherapeutic Albumin-Flt3L enhances antigen-specific immunity and tumor control following chemoradiation: An analysis of underlying mechanism
AMER ASSOC IMMUNOLOGISTS. 2021
View details for Web of Science ID 000713665800371
A novel pseudovirus-based mouse model of SARS-CoV-2 infection to test COVID-19 interventions
JOURNAL OF BIOMEDICAL SCIENCE
2021; 28 (1): 34
The spread of SARS-CoV-2, the virus that causes Coronavirus Disease 2019 (COVID-19), has been characterized as a worldwide pandemic. Currently, there are few preclinical animal models that suitably represent infection, as the main point of entry to human cells is via human angiotensin-converting enzyme 2 (ACE2) which is not present in typical preclinical mouse strains. Additionally, SARS-CoV-2 is highly virulent and unsafe for use in many research facilities. Here we describe the development of a preclinical animal model using intranasal administration of ACE2 followed by non-infectious SARS-CoV-2 pseudovirus (PsV) challenge.To specifically generate our SARS-CoV-2 PsV, we used a lentivirus system. Following co-transfection with a packaging plasmid containing HIV Gag and Pol, luciferase-expressing lentiviruses, and a plasmid carrying the SARS-CoV-2 spike protein, SARS-CoV-2 PsVs can be isolated and purified. To better understand and maximize the infectivity of SARS-CoV-2 PsV, we generated PsV carrying spike protein variants known to have varying human ACE2 binding properties, including 19 deletion (19del) and 19del + D614G.Our system demonstrated the ability of PsVs to infect the respiratory passage of mice following intranasal hACE2 transduction. Additionally, we demonstrate in vitro and in vivo manipulability of our system using recombinant receptor-binding domain protein to prevent PsV infection.Our PsV system is able to model SARS-CoV-2 infections in a preclinical mouse model and can be used to test interventions or preventative treatments. We believe that this method can be extended to work in various mouse strains or to model infection with different coronaviruses. A simple in vivo system such as our model is crucial for rapidly and effectively responding to the current COVID-19 pandemic in addition to preparing for future potential coronavirus outbreaks.
View details for DOI 10.1186/s12929-021-00729-3
View details for Web of Science ID 000645634400001
View details for PubMedID 33926459
View details for PubMedCentralID PMC8084690
In vivo characterization of emerging SARS-CoV-2 variant infectivity and human antibody escape potential.
2021; 37 (3): 109838
As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads, variants with enhanced virulence and transmissibility have emerged. Although in vitro systems allow rapid characterization, they do not fully recapitulate the dynamic interaction of virions and neutralizing antibodies in the airway. Here, we demonstrate that the N501Y variant permits respiratory infection in unmodified mice. We utilize N501Y to survey in vivo pseudovirus infection dynamics and susceptibility to reinfection with the L452R (Los Angeles), K417N + E484K (South Africa), and L452R + K417N + E484Q (India) variants. Human coronavirus disease 2019 (COVID-19)+ or vaccinated antibody isotypes, titers, variant receptor binding domain (RBD) binding, and neutralization potential are studied, revealing numerous significant correlations. Immune escape of the K417N + E484K variant is observed because infection can be appreciated in the nasopharynx, but not lungs, of mice transferred with low-antibody-tier plasma. Conversely, near-complete protection is observed in animals receiving high-antibody-tier plasma, a phenomenon that can only be appreciated in vivo.
View details for DOI 10.1016/j.celrep.2021.109838
View details for PubMedID 34648735
View details for PubMedCentralID PMC8491932
Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors.
2021; 16 (9): e0256937
Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.
View details for DOI 10.1371/journal.pone.0256937
View details for PubMedID 34506530
View details for PubMedCentralID PMC8432795
Delivery of IL-2 to the T Cell Surface Through Phosphatidylserine Permits Robust Expansion of CD8 T Cells.
Frontiers in immunology
2021; 12: 755995
The phospholipid phosphatidylserine (PS) is naturally maintained on the cytoplasmic side of the plasma membrane. Independent of apoptosis, PS is redistributed to the surface of CD8 T cells in response to TCR-mediated activation. Annexin V (AnnV) is a protein known to bind PS with high affinity and has been effectively utilized to anchor antigen to the surface of CD8 T cells. To expand these studies, we aimed to exploit TCR activation driven PS exposure as a target to deliver cytokine, namely interleukin-2 (IL-2), to the surface of CD8 T cells. This was accomplished using a novel chimeric fusion protein of annexin V and interleukin 2 (AnnV-IL2). In vitro analysis revealed that AnnV-IL2 is able to specifically bind PS on the T cell surface following TCR stimulation. Consequently, AnnV-IL2 proved to be significantly more effective at enhancing T cell activation compared to recombinant IL-2. In vivo, AnnV-IL2 promotes robust expansion of antigen-specific cells capable of interferon gamma (IFNγ) production when administered following peptide vaccination. Importantly, upon antigen rechallenge, AnnV-IL2 treatment mice demonstrated a stronger secondary expansion, indicating durability of AnnV-IL2 mediated responses. Our data supports the use of AnnV-IL2 to modulate antigen-specific T cell immunity and demonstrates that the PS-AnnV axis is a feasible mechanism to target diverse cargo to CD8 T cells.
View details for DOI 10.3389/fimmu.2021.755995
View details for PubMedID 34804041
View details for PubMedCentralID PMC8599986
Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model.
2021; 11 (1): 6354
Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.
View details for DOI 10.1038/s41598-021-86017-4
View details for PubMedID 33737712
View details for PubMedCentralID PMC7973732
Development of a Novel Mouse Model of Spontaneous High-Risk HPVE6/E7-Expressing Carcinoma in the Cervicovaginal Tract.
2021; 81 (17): 4560-4569
Current preclinical models for cervical cancer lack important clinical and pathologic features. To improve upon these models, we aimed to develop a novel, spontaneous HPV16-expressing carcinoma model that captures major aspects of HPV-associated cancer in the female genital tract. This novel preclinical model features (i) expression of HPV oncogenes E6 and E7 in the tumors in female reproductive tract of mice, (ii) spontaneous progression through high-grade squamous intraepithelial lesion (HSIL) to carcinoma, and (iii) flexibility to model cancers from different high-risk HPV genotypes. This was accomplished by injecting plasmids expressing HPV16 E6/E7-luciferase, AKT, c-myc, and Sleeping Beauty transposase into the cervicovaginal tract of C57BL/6 mice followed by electroporation. Cell lines derived from these tumors expressed HPV16 E6/E7 oncogenes, formed tumors in immunocompetent mice, and displayed carcinoma morphology. In all, this novel HPV-associated cervicogenital carcinoma model and HPV16E6/E7-expressing tumor cell line improves upon current HPV16-E6/E7-expressing tumor models. These tumor models may serve as important preclinical models for the development of therapeutic HPV vaccines or novel therapeutic interventions against HPV E6/E7-expressing tumors. SIGNIFICANCE: This study describes the development of a clinically relevant mouse model of cervicovaginal carcinoma that progresses from high-grade lesions and recapitulates key features of human HPV+ cervical cancer.
View details for DOI 10.1158/0008-5472.CAN-21-0399
View details for PubMedID 34215618
View details for PubMedCentralID PMC8416934
Promotion of cross-presenting DC expansion in humanized mice and antigen-specific immunity in murine models of vaccination and cancer by Albumin-Flt3L
AMER ASSOC IMMUNOLOGISTS. 2020
View details for Web of Science ID 000589972400653
NKG2D-Fc fusion protein promotes antitumor immunity through the depletion of immunosuppressive cells.
Cancer immunology, immunotherapy : CII
2020; 69 (10): 2147-2155
A major factor impeding the success of numerous therapeutic approaches in cancer is the immunosuppressive nature of the tumor microenvironment (TME). Hence, methods capable of reverting tumor immunosuppression through depletion or reprogramming of myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs) are of great clinical need. Here, we explore NKG2D-Fc as a modality to modulate antitumor immunity through the depletion of immunosuppressive MDSCs and Tregs in the TME. We have generated the NKG2D-Fc fusion protein and characterized its potential to mediate tumor control and overall survival in LL2 and MC38 murine models. Upon treatment of LL2 or MC38 tumor-bearing mice with NKG2D-Fc, we observe significant tumor control and enhanced survival compared to Fc control. When characterizing MDCSs and Tregs from tumor-bearing mice, we observe clear expression of NKG2D-ligand RAE1γ and subsequent binding of NKG2D-Fc fusion protein to both MDSCs and Tregs. Examining the immune profile of mice treated with NKG2D-Fc reveals significant depletion of MDSCs and Tregs in the TME, as well as an increase in NK cells likely due to the reversed suppressive TME. In conclusion, NKG2D-Fc induces antitumor immunity and tumor control through the depletion of MDSCs and Tregs, subsequently providing a niche for the infiltration and expansion of proinflammatory cells, such as NK cells. Strategies capable of modulating the immunosuppressive state in cancer are in high clinical demand. NKG2D-Fc is a simple, single tool capable of depleting both MDSCs and Tregs and should be further investigated as a therapeutic agent for the treatment of cancer.
View details for DOI 10.1007/s00262-020-02615-7
View details for PubMedID 32468232
View details for PubMedCentralID PMC7529872
Molecular Characteristics of Rickettsia in Ticks Collected along the Southern Border of Mongolia.
Pathogens (Basel, Switzerland)
2020; 9 (11)
Tick-borne infections are a significant threat to public health, particularly in regions where individuals frequently enter tick habitats. Roughly 26% of the population in Mongolia practice nomadic pastoralism and are considered at high risk of exposure to ticks and the diseases they carry. This study tested ticks from Mongolia's southern border for Rickettsia spp. to better understand the epidemiology of tick-borne diseases in the region. Dermacentor nuttalli and Hyalomma asiaticum ticks (n = 4022) were pooled and tested for Rickettsia spp. by real-time PCR. Melt-curve analyses and Sanger sequencing were used to identify Rickettsia species. Approximately 64% of the 786 tick pools tested positive for Rickettsia bacteria. Melt curve analyses identified four different Rickettsia species circulating in these tick pools. Amplicon sequencing of the ompA gene identified Rickettsia spp. that closely resembled R. raoultii and R. sibirica. Dermacentor nuttalli ticks from Govi-Altai had the highest maximum likelihood estimation infection rate 48.4% (95% CI: 41.7-56.5%), while Hyalommaasiaticum collected in Omnogovi had a rate of 7.6% (95% CI: 6.2-9.2%). The high detection of Rickettsia suggests a substantial risk of infection in southern Mongolia. Further studies are necessary to investigate the clinical burden of tick-borne diseases in Mongolia.
View details for DOI 10.3390/pathogens9110943
View details for PubMedID 33202715
View details for PubMedCentralID PMC7696098
Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis.
Journal for immunotherapy of cancer
2020; 8 (1)
Peritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat clinically due to widespread tumor dissemination in the peritoneal cavity.We developed a clinically relevant, genetically induced, peritoneal carcinomatosis model that recapitulates the histological morphology and immunosuppressive state of the tumor microenvironment of metastatic peritoneal HGSCs by intraperitoneally injecting shp53, AKT, c-Myc, luciferase and sleeping beauty transposase, followed by electroporation (EP) in the peritoneal cavity of immunocompetent mice (intraperitoneal (IP)/EP mice).Similar to the spread of human ovarian cancers, IP/EP mice displayed multiple tumor nodules attached to the surface of the abdomen. Histopathological analysis indicated that these tumors were epithelial in origin. These IP/EP mice also displayed a loss of CD3+ T cell infiltration in tumors, highly expressed inhibitory checkpoint molecules in tumor-infiltrating and global CD4+ and CD8+ T cells, and increased levels of transforming growth factor-β in the ascites, all of which contribute to the promotion of tumor growth.Overall, our tumor model recapitulates clinical peritoneal HGSC metastasis, which makes it ideal for preclinical drug screening, testing of immunotherapy-based therapeutics and studying of the tumor biology of peritoneal carcinomatosis.
View details for DOI 10.1136/jitc-2019-000480
View details for PubMedID 32111730
View details for PubMedCentralID PMC7057437
Annexin A5 as an immune checkpoint inhibitor and tumor-homing molecule for cancer treatment.
2020; 11 (1): 1137
The interaction between immune cells and phosphatidylserine (PS) molecules exposed on the surface of apoptotic-tumor bodies, such as those induced by chemotherapies, contributes to the formation of an immunosuppressive tumor microenvironment (TME). Annexin A5 (AnxA5) binds with high affinity to PS externalized by apoptotic cells, thereby hindering their interaction with immune cells. Here, we show that AnxA5 administration rescue the immunosuppressive state of the TME induced by chemotherapy. Due to the preferential homing of AnxA5 to the TME enriched with PS+ tumor cells, we demonstrate in vivo that fusing tumor-antigen peptide to AnxA5 significantly enhances its immunogenicity and antitumor efficacy when administered after chemotherapy. Also, the therapeutic antitumor effect of an AnxA5-peptide fusion can be further enhanced by administration of other immune checkpoint inhibitors. Our findings support the administration of AnxA5 following chemotherapy as a promising immune checkpoint inhibitor for cancer treatment.
View details for DOI 10.1038/s41467-020-14821-z
View details for PubMedID 32111835
View details for PubMedCentralID PMC7048819
Albumin-Flt3L-induced cross-presenting dendritic cells promote neoantigen-specific antitumor immunity and subsequent tumor control in murine models of cancer
AMER ASSOC IMMUNOLOGISTS. 2019
View details for Web of Science ID 000524982500315
INVESTIGATING THE PREVALENCE OF PREVIOUS SPOTTED FEVER GROUP RICKETTSIA EXPOSURE ALONG THE SOUTHERN BORDER OF MONGOLIA
AMER SOC TROP MED & HYGIENE. 2019: 38
View details for Web of Science ID 000507364502121
TLR9 acts as a sensor for tumor-released DNA to modulate anti-tumor immunity after chemotherapy.
Journal for immunotherapy of cancer
2019; 7 (1): 260
The tumor microenvironment exists in a state of dynamic equilibrium, in which a balance of agonist and antagonist signals govern the anti-tumor immune responses. Previous studies have shown that chemotherapy could shift this balance in favor of agonistic signals for the anti-tumor immune responses mounted by CD8+ cytotoxic T lymphocytes (CTL), providing sufficiently high antigen density within the tumor. We undertook the current study to characterize the anti-tumor immune response following chemotherapy and its underlying mechanisms. We show that this 'adjuvant effect' of chemotherapy is, at least partially, mediated by the release of tumor DNA and acts through the Toll-like receptor 9 (TLR9) pathway. We found that tumor-released DNA causes accumulation, antigen uptake, and maturation of dendritic cells (DCs) in the tumor in a TLR9-dependent manner. These DCs subsequently migrate into the draining lymph nodes and prime tumor-specific CTLs. Our study provides novel insights to the molecular and cellular mechanisms by which chemotherapy converts the tumor microenvironment into a site permissive for the activation of a potent tumor-specific adaptive immune response.
View details for DOI 10.1186/s40425-019-0738-2
View details for PubMedID 31619293
View details for PubMedCentralID PMC6794732
mTORC1 feedback to AKT modulates lysosomal biogenesis through MiT/TFE regulation.
The Journal of clinical investigation
2019; 129 (12): 5584-5599
The microphthalmia family of transcription factors (MiT/TFEs) controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. However, the mechanisms by which cells with constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we found that epidermal Tsc1 deletion resulted in a phenotype characterized by wavy hair and curly whiskers, and was associated with increased EGFR and HER2 degradation. Unexpectedly, constitutive mTORC1 activation with Tsc1 loss increased lysosomal content via upregulated expression and activity of MiT/TFEs, whereas genetic deletion of Rheb or Rptor or prolonged pharmacologic mTORC1 inactivation had the reverse effect. This paradoxical increase in lysosomal biogenesis by mTORC1 was mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE downregulation. Thus, inhibiting hyperactive AKT signaling in the context of mTORC1 loss-of-function fully restored MiT/TFE expression and activity. These data suggest that signaling feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling, respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling.
View details for DOI 10.1172/JCI128287
View details for PubMedID 31527310
View details for PubMedCentralID PMC6877313
Type-1 Interferons Impair the Immunoregulatory Activity of IL-10: Understanding the Mechanisms of Abrogation of Transplant Tolerance
LIPPINCOTT WILLIAMS & WILKINS. 2018: S51
View details for DOI 10.1097/01.tp.0000542615.17196.d9
View details for Web of Science ID 000444541200084
Type-1 interferon impairs the immunoregulatory activity of IL-10: Understanding the mechanisms of abrogation of transplant tolerance
AMER ASSOC IMMUNOLOGISTS. 2018
View details for Web of Science ID 000459977704002
MOLECULAR CHARACTERISTICS OF RICKETTSIA IN TICKS COLLECTED ALONG THE SOUTHERN BORDER OF MONGOLIA
AMER SOC TROP MED & HYGIENE. 2018: 262
View details for Web of Science ID 000461386603167
Type-I Interferons Inhibit Interleukin-10 Signaling and Favor Type 1 Diabetes Development in Nonobese Diabetic Mice.
Frontiers in immunology
2018; 9: 1565
Destruction of insulin-producing β-cells by autoreactive T lymphocytes leads to the development of type 1 diabetes. Type-I interferons (TI-IFN) and interleukin-10 (IL-10) have been connected with the pathophysiology of this disease; however, their interplay in the modulation of diabetogenic T cells remains unknown. We have discovered that TI-IFN cause a selective inhibition of IL-10 signaling in effector and regulatory T cells, altering their responses. This correlates with diabetes development in nonobese diabetic mice, where the inhibition is also spatially localized to T cells of pancreatic and mesenteric lymph nodes. IL-10 signaling inhibition is reversible and can be restored via blockade of TI-IFN/IFN-R interaction, paralleling with the resulting delay in diabetes onset and reduced severity. Overall, we propose a novel molecular link between TI-IFN and IL-10 signaling that helps better understand the complex dynamics of autoimmune diabetes development and reveals new strategies of intervention.
View details for DOI 10.3389/fimmu.2018.01565
View details for PubMedID 30061883
View details for PubMedCentralID PMC6054963
Interferon-gamma signaling inhibition by a suppressor of cytokine signaling-1 (SOCS-1) mimetic peptide ameliorates lupus pathology in a spontaneous mouse model.
AMER ASSOC IMMUNOLOGISTS. 2016
View details for Web of Science ID 000380288302345
Sparse serological evidence of Plasmodium vivax transmission in the Ouest and Sud-Est departments of Haiti.
2016; 162: 27-34
Plasmodium vivax infections, while quite prevalent throughout South and Central America, are virtually non-existent in Haiti, where P. falciparum infections are detected in over 99% of malaria cases. Historically, few cases of P. vivax have been reported in Haiti; all of which were identified by microscopy and none were confirmed by molecular diagnostics. To further examine the transmission of P. vivax in Haiti, a cross-sectional seroepidemiological study was conducted.Whole blood was collected from 814 community members and school children ranging in age between 2 and 80 years-of-age from four locations in the Ouest and Sud-Est Departments of Haiti. After separation of serum, samples were screened for antibodies toward P. vivax apical membrane antigen (AMA-1) and merozoite surface protein-119 (MSP-1) using an indirect enzyme-linked immunosorbent assay (ELISA).Of all participants screened, 4.42% (36/814) were seropositive for AMA-1, 4.55% (37/814) were seropositive for MSP-1, 7.99% (65/814) were seropositive to either antigen, and only 0.98% (7/814) were seropositive for both antigens. Seroconversion rates (SCR) for AMA-1, MSP-1, either AMA-1 or MSP-1, and for both AMA-1 and MSP-1 estimated from the cross-sectional seroprevalence indicated rates of P. vivax transmission of less than 1% per year.Given the lack of historical evidence of P. vivax infections on the island of Hispaniola, the sparse serological evidence of antibodies toward P. vivax identified in the current study further support the notion that the transmission of P. vivax malaria might be extremely low or even completely absent in Haiti.
View details for DOI 10.1016/j.actatropica.2016.05.011
View details for PubMedID 27230796
Aberrant IL-17 production, mediated by SOCS1 deficiency, promotes inflammatory skin pathologies and lymphadenopathy in an IFN gamma independent manner.
AMER ASSOC IMMUNOLOGISTS. 2015
View details for Web of Science ID 000379404500006
Dysregulated cytokine production by leukocytes, mediated by SOCS1 deficiency, is correlated to skin pathology: implications for therapeutic targeting.
AMER ASSOC IMMUNOLOGISTS. 2014
View details for Web of Science ID 000209765005249
Age-specific malaria seroprevalence rates: a cross-sectional analysis of malaria transmission in the Ouest and Sud-Est departments of Haiti.
2014; 13: 361
Malaria transmission continues to occur in Haiti, with 25,423 confirmed cases of Plasmodium falciparum and 161,236 suspected infections reported in 2012. At low prevalence levels, passive surveillance measures, which rely primarily on reports from health systems, becomes less appropriate for capturing annual malaria incidence. To improve understanding of malaria transmission in Haiti, participants from the Ouest and Sud-Est departments were screened using a highly sensitive enzyme-linked immunosorbent assay (ELISA).Between February and May 2013, samples were collected from four different sites including a rural community, two schools, and a clinic located in the Ouest and Sud-Est departments of Haiti. A total of 815 serum samples were screened for malaria antibodies using an indirect ELISA coated with vaccine candidates apical membrane antigen (AMA-1) and merozoite surface protein-1 (MSP-119). The classification of previous exposure was established by using a threshold value that fell three standard deviations above the mean absorbance for suspected seronegative population members (OD of 0.32 and 0.26 for AMA-1 and MSP-1, respectively). The observed seroprevalence values were used to fit a modified reverse catalytic model to yield estimates of seroconversion rates.Of the samples screened, 172 of 815 (21.1%) were AMA-1 positive, 179 of 759 (23.6%) were MSP-119 positive, and 247 of 815 (30.3%) were positive for either AMA-1 or MSP-1; indicating rates of previous infections between 21.1% and 30.3%. Not surprisingly, age was highly associated with the likelihood of previous infection (p-value <0.001). After stratification by age, the estimated seroconversion rate indicated that the annual malaria transmission in the Ouest and Sud-Est department is approximately 2.5% (95% CI SCR: 2.2%, 2.8%).These findings suggest that despite the absence of sustained malaria control efforts in Haiti, transmission has remained relatively low over multiple decades. Elimination in Haiti appears to be feasible; however, surveillance must continue to be strengthened in order to respond to areas with high transmission and measure the impact of future interventions.
View details for DOI 10.1186/1475-2875-13-361
View details for PubMedID 25218803
View details for PubMedCentralID PMC4172790
Th17 cells in immunity and autoimmunity.
Clinical & developmental immunology
2013; 2013: 986789
Th17 and IL-17 play important roles in the clearance of extracellular bacterial and fungal infections. However, strong evidence also implicates the Th17 lineage in several autoimmune disorders including multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and asthma. The Th17 subset has also been connected with type I diabetes, although whether it plays a role in the pathogenicity of or protection from the disease remains a controversial issue. In this review we have provided a comprehensive overview of Th17 pathogenicity and function, including novel evidence for a protective role of Th17 cells in conjunction with the microbiota gut flora in T1D onset and progression.
View details for DOI 10.1155/2013/986789
View details for PubMedID 24454481
View details for PubMedCentralID PMC3886602