TY  - JOUR
AB  - INTRODUCTION: BTZ-043 is a promising novel drug candidate for anti-tuberculosis treatment. This study aimed to apply a previously developed mouse-to-human translational modeling platform for anti-tuberculosis drugs to predict phase IIA outcomes for BTZ-043 in humans and evaluate the impact of observed drug-drug interactions on the contribution of BTZ-043 to combotherapy in a mouse model. METHODS: The study utilized data from mouse experiments for BTZ-043 monotherapy and combotherapy with bedaquiline, pretomanid, and linezolid, and clinical information for BTZ-043 monotherapy. The translational models were applied to predict the colony-forming units as a measure of efficacy in humans treated with BTZ-043 monotherapy and evaluate the effect of BTZ-043 on the pharmacokinetics-pharmacodynamics of combotherapy bedaquiline, pretomanid, and linezolid. RESULTS: The mouse-pharmacokinetic and mouse-pharmacodynamic data for BTZ-043 monotherapy were best described by two-compartmental and direct Emax models, respectively. The model-based prediction of efficacy in humans was comparable to the observed phase IIA efficacy. Single-compartmental models, developed separately, best described the mouse-pharmacokinetic data for bedaquiline, pretomanid, and linezolid in combotherapy. Co-administration with BTZ-043 was associated with at least a 2-fold reduction in bedaquiline, pretomanid, and linezolid exposures in mice, and model-based simulations suggested that the observed decreases in exposure to these drugs would have resulted in even lower efficacy than what was observed when BPaL is co-administered with BTZ-043. CONCLUSION: The translational modeling platform adequately predicted the efficacy of BTZ-043 monotherapy. In the absence of drug-drug interactions, co-administration of BTZ-043 with bedaquiline, pretomanid, and linezolid in combotherapy is predicted to improve treatment efficacy.
AU  - Ngara, B.*
AU  - Flori, L.*
AU  - van Wijk, R.C.*
AU  - Ernest, J.P.*
AU  - Tyagi, S.*
AU  - Soni, H.*
AU  - Hölscher, C.*
AU  - Walter, K.*
AU  - Dreisbach, J.*
AU  - Hoelscher, M.
AU  - Nuermberger, E.L.*
AU  - Savic, R.*
C1  - 73397
C2  - 57046
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - e901-e911
TI  - Translational modeling of BTZ-043 in predicting phase IIA efficacy and evaluating drug-drug interactions with BPaL in murine models.
JO  - J. Infect. Dis.
VL  - 231
IS  - 5
PB  - Oxford Univ Press Inc
PY  - 2025
SN  - 0022-1899
ER  - 

TY  - JOUR
AB  - Background. Chronic hepatitis B develops more frequently in countries with high prevalence of helminth infections. The crosstalk between these 2 major liver-residing pathogens, Schistosoma mansoni and hepatitis B virus (HBV), is barely understood.Methods. We used state-of-the-art models for both acute and chronic HBV infection to study the pathogen-crosstalk during the different immune phases of schistosome infection.Results. Although liver pathology caused by schistosome infection was not affected by either acute or chronic HBV infection, S mansoni infection influenced HBV infection outcomes in a phase-dependent manner. Interferon (IFN)-gamma secreting, HBV- and schistosome-specific CD8 T cells acted in synergy to reduce HBV-induced pathology during the T(H)1 phase and chronic phase of schistosomiasis. Consequently, HBV was completely rescued in IFN-gamma-deficient or in T(H)2 phase coinfected mice demonstrating the key role of this cytokine. It is interesting to note that secondary helminth infection on the basis of persistent (chronic) HBV infection increased HBV-specific T-cell frequency and resulted in suppression of virus replication but failed to fully restore T-cell function and eliminate HBV.Conclusions. Thus, schistosome-induced IFN-gamma had a prominent antiviral effect that outcompeted immunosuppressive effects of T(H)2 cytokines, whereas HBV coinfection did not alter schistosome pathogenicity.
AU  - Loffredo-Verde, E.
AU  - Bhattacharjee, S.*
AU  - Malo, A.
AU  - Festag, J.
AU  - Kosinska, A.
AU  - Ringelhan, M.*
AU  - Rim Sarkar, S.*
AU  - Steiger, K.*
AU  - Heikenwälder, M.
AU  - Protzer, U.
AU  - Prazeres da Costa, C.U.*
C1  - 57718
C2  - 47886
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 1448-1461
TI  - Dynamic, helminth-induced immune modulation influences the outcome of acute and chronic hepatitis B virus infection.
JO  - J. Infect. Dis.
VL  - 221
IS  - 9
PB  - Oxford Univ Press Inc
PY  - 2020
SN  - 0022-1899
ER  - 

TY  - JOUR
AB  - Background. Type III interferons (IFNs) (lambda 1-3) activate similar signaling cascades as type I IFNs (alpha and beta) via different receptors. Since IFN-alpha and lymphotoxin-beta activate cytosine deamination and subsequent purging of nuclear hepatitis B virus (HBV) DNA, we investigated whether IFN-beta and -lambda may also induce these antiviral effects in differentiated HBV-infected hepatocytes.Methods. After determining the biological activity of IFN-alpha 2,-beta 1, -lambda 1, and -lambda 2 in differentiated hepatocytes, their antiviral effects were analyzed in HBV-infected primary human hepatocytes and HepaRG cells.Results. Type I and III IFNs reduced nuclear open-circle DNA and covalently closed circular DNA (cccDNA) levels in HBV-infected cells. IFN-beta and -lambda were at least as efficient as IFN-alpha. Differential DNA-denaturing polymerase chain reaction and sequencing analysis revealed G-to-A sequence alterations of HBV cccDNA in IFN-alpha, -beta, and -lambda-treated liver cells indicating deamination. All IFNs induced apolipoprotein B messenger RNA-editing enzyme-catalytic polypeptide-like (APOBEC) deaminases 3A and 3G within 24 hours of treatment, but IFN-beta and -lambda induced longer-lasting expression of APOBEC deaminases in comparison to IFN-alpha.Conclusions. IFN-beta, IFN-lambda 1, and IFN-lambda 2 induce cccDNA deamination and degradation at least as efficiently as IFN-alpha, indicating that these antiviral cytokines are interesting candidates for the design of new therapeutic strategies aiming at cccDNA reduction and HBV cure.
AU  - Bockmann, J.H.
AU  - Stadler, D.
AU  - Xia, Y.
AU  - Ko, C.
AU  - Wettengel, J.M.
AU  - Zur Wiesch, J.S.*
AU  - Dandri, M.*
AU  - Protzer, U.
C1  - 55786
C2  - 46546
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 567-577
TI  - Comparative analysis of the antiviral effects mediated by type I and III interferons in hepatitis B virus infected hepatocytes.
JO  - J. Infect. Dis.
VL  - 220
IS  - 4
PB  - Oxford Univ Press Inc
PY  - 2019
SN  - 0022-1899
ER  - 

TY  - JOUR
AB  - BACKGROUND:  Universal two-dose hepatitis A virus (HAV) vaccination of toddlers effectively controls hepatitis A. High vaccine costs impede, however, implementation in endemic countries. To test single-dose vaccination as a possible alternative, we initiated an observational, longitudinal study in Nicaragua, to assess protective effectiveness and - through challenge vaccination - humoral immune memory response. METHODS:  Following a 2003 serosurvey, 130 originally seronegative children received 2005 one dose virosomal HAV vaccine, followed by yearly serological and clinical assessments until 2012. After 7.5 years, a vaccine booster was administered. Concurrent antibody screening of patients presenting with hepatitis symptoms documented persistent HAV circulation in the communities studied. RESULTS:  Between serosurvey and vaccination, 25 children contracted hepatitis A subclinically (>8,000 mIU/mL anti-HAV). In the remaining 105 children, immunisation resulted in 17-572 mIU/mL anti-HAV. Under the ≥15% annual infection risk, an estimated 60% of children were exposed to HAV encounters during follow-up. No child presented with hepatitis symptomatology. Serological breakthrough infection (7106 mIU/mL) was documented in one child, representing an estimated 98.3% (95%CI, 87.9-99.8) protective effectiveness. Boosting elicited an average 29.7-fold increase of anti-HAV levels. CONCLUSIONS:  In children living in hyperendemic settings, one dose of virosomal HAV vaccine is sufficient to activate immune memory and may provide long-term protection.
AU  - Mayorga, O.*
AU  - Bühler, S.*
AU  - Jaeger, V.K.*
AU  - Bally, S.*
AU  - Hatz, C.*
AU  - Frösner, G.
AU  - Protzer, U.
AU  - van Damme, P.*
AU  - Egger, M.*
AU  - Herzog, C.*
C1  - 49387
C2  - 41810
CY  - Cary
SP  - 1498-1506
TI  - Single dose hepatitis A immunisation: 7.5 year observational pilot study in Nicaraguan children to assess protective effectiveness and humoral immune memory response.
JO  - J. Infect. Dis.
VL  - 214
IS  - 10
PB  - Oxford Univ Press Inc
PY  - 2016
SN  - 0022-1899
ER  - 

TY  - JOUR
AB  - BACKGROUND:  Universal 2-dose hepatitis A virus (HAV) vaccination of toddlers effectively controls hepatitis A. High vaccine costs, however, impede implementation in endemic countries. To test single-dose vaccination as a possible alternative, we initiated an observational, longitudinal study in Nicaragua, to assess protective effectiveness and-through challenge vaccination-humoral immune memory response. METHODS:  After a 2003 serosurvey, 130 originally seronegative children received one dose of virosomal HAV vaccine in 2005, followed by yearly serological and clinical assessments until 2012. After 7.5 years, a vaccine booster was administered. Concurrent antibody screening of patients presenting with hepatitis symptoms documented persistent HAV circulation in the communities studied. RESULTS:  Between serosurvey and vaccination, 25 children contracted hepatitis A subclinically (>8000 mIU/mL anti-HAV). In the remaining 105 children, immunization resulted in anti-HAV levels of 17-572 mIU/mL. Based on the ≥15% annual infection risk, an estimated 60% of children were exposed to HAV encounters during follow-up. No child presented with hepatitis symptoms. Serological breakthrough infection (7106 mIU/mL) was documented in 1 child, representing an estimated protective effectiveness of 98.3% (95% confidence interval, 87.9-99.8). Boosting elicited an average 29.7-fold increase of anti-HAV levels. CONCLUSIONS:  In children living in hyperendemic settings, a single dose of virosomal HAV vaccine is sufficient to activate immune memory and may provide long-term protection.
AU  - Mayorga, O.*
AU  - Bühler, S.*
AU  - Jaeger, V.K.*
AU  - Bally, S.*
AU  - Hatz, C.*
AU  - Frösner, G.
AU  - Protzer, U.
AU  - van Damme, P.*
AU  - Egger, M.*
AU  - Herzog, C.*
C1  - 50104
C2  - 42334
SP  - 1498-1506
TI  - Single-dose Hepatitis A immunization: 7.5-year observational pilot study in nicaraguan children to assess protective effectiveness and humoral immune memory response.
JO  - J. Infect. Dis.
VL  - 214
IS  - 10
PY  - 2016
SN  - 0022-1899
ER  - 

TY  - JOUR
AB  - Many enveloped viruses, including herpes viruses, hepatitis B virus (HBV), and hepatitis C virus (HCV), and human immunodeficiency virus (HIV), are among the most important human pathogens and are often responsible for coinfections involving >= 2 types of viruses. However, therapies that are effective against multiple virus classes are rare. Here we present a new class of synthetic anti-lipopolysaccharide peptides (SALPs) that bind to heparan sulfate moieties on the cell surface and inhibit infection with a variety of enveloped viruses. We demonstrate that SALPs inhibit entry of human immunodeficiency virus type 1 (HIV-1), herpes simplex virus (HSV) 1 and 2, HBV, and HCV to their respective host cells. Despite their high antiviral efficiency, SALPs were well tolerated, and neither toxicity nor measurable inhibitor-induced adverse effects were observed. Since these broad-spectrum antiviral peptides target a host cell rather than a viral component, they may also be useful for suppression of viruses that are resistant to antiviral drugs.
AU  - Krepstakies, M.*
AU  - Lucifora, J.
AU  - Nagel, C.H.*
AU  - Zeisel, M.B.*
AU  - Holstermann, B.*
AU  - Hohenberg, H.*
AU  - Kowalska, I.*
AU  - Gutsmann, T.*
AU  - Baumert, T.F.*
AU  - Brandenburg, K.*
AU  - Hauber, J.*
AU  - Protzer, U.
C1  - 7955
C2  - 30022
SP  - 1654-1664
TI  - A new class of synthetic peptide inhibitors blocks attachment and entry of human pathogenic viruses.
JO  - J. Infect. Dis.
VL  - 205
IS  - 11
PB  - Oxford Univ. Press Inc.
PY  - 2012
SN  - 0022-1899
ER  - 

TY  - JOUR
AB  - The obligate intracellular development of Chlamydia suggests that the bacteria should be vulnerable to premature host cell apoptosis, but because Chlamydia-infected cells are apoptosis resistant, this has never been able to be tested. We have devised a system to circumvent the apoptotic block imposed by chlamydial infection. When the proapoptotic protein BimS was experimentally induced, epithelial cells underwent apoptosis that was not blocked by chlamydial infection. Apoptosis during the developmental cycle prevented the generation of infectious bacteria and caused transcriptional changes of bacterial genes and loss of intracellular ATP. Intriguingly, although apoptosis resulted in destruction of host cell structures and of the Chlamydia inclusion, and prevented generation of elementary bodies, BimS induction in the presence of a caspase inhibitor allowed differentiation into morphologically normal but noninfectious elementary bodies. These data show that chlamydial infection renders host cells apoptosis resistant at a premitochondrial step and demonstrate the consequences of premature apoptosis for development of the bacteria.
AU  - Ying, S.*
AU  - Pettengill, M.*
AU  - Latham, E.R.*
AU  - Walch, A.K.
AU  - Ojcius, D.M.*
AU  - Häcker, G.*
C1  - 655
C2  - 25765
SP  - 1536-1544
TI  - Premature apoptosis of Chlamydia-infected cells disrupts chlamydial development.
JO  - J. Infect. Dis.
VL  - 198
IS  - 10
PB  - Univ. of Chicago Press
PY  - 2008
SN  - 0022-1899
ER  - 

TY  - JOUR
AU  - Frank, O.*
AU  - Jones-Brando, L.*
AU  - Leib-Mösch, C.
AU  - Yolken, R.*
AU  - Seifarth, W.*
C1  - 4440
C2  - 24129
SP  - 1447-1449
TI  - Altered transcriptional activity of human endogenous retroviruses in neuroepithelial cells after infection with Toxoplasma gondii.
JO  - J. Infect. Dis.
VL  - 194
PY  - 2006
SN  - 0022-1899
ER  - 

TY  - JOUR
AB  - The aim of this study is to analyze the dynamics of the mouse cytomegalovirus (MCMV)-dendritic cell (DC) interaction. Immature and mature DCs derived from the mouse stem cell line factor-dependent cell Paterson mixed potential were infected with a recombinant MCMV expressing green fluorescent protein. Infection of immature DCs resulted in DC activation and virus production, both of which may contribute to viral dissemination. The infection of mature DCs was nonproductive and was restricted to immediate-early and early viral protein expression. During early stages of MCMV infection, mature DCs up-regulated major histocompatibility complex (MHC) and costimulatory molecules and activated autologous, but not allogeneic, naive T cells. At later times of MCMV infection, DCs prevented T cell activation by down-regulation of MHC and costimulatory molecules. Thus, DCs under the influence of MCMV have a physiologic dual role: to initiate and to restrict T cell activation. The lack of immunostimulation in allogeneic settings may explain the increased risk of MCMV morbidity after allogeneic transplantation.
AU  - Mathys, S.*
AU  - Schroeder, T.
AU  - Ellwart, J.
AU  - Koszinowski, U.H.*
AU  - Messerle, M.*
AU  - Just, U.
C1  - 22249
C2  - 21010
SP  - 988-999
TI  - Dendritic Cells under Influence of Mouse Cytomegalovirus Have a Physiologic Dual Role : To Initiative and to Restrict T Cell Activation.
JO  - J. Infect. Dis.
VL  - 187
IS  - 6
PY  - 2003
SN  - 0022-1899
ER  -