Prior aerosol infection with lineage A SARS-CoV-2 variant protects hamsters from disease, but not reinfection with B.1.351 SARS-CoV-2 variant

Anti-inflammatory treatment of chronic inflammatory diseases often increases susceptibility to infectious diseases such as tuberculosis (TB). Since numerous chronic inflammatory and autoimmune diseases are mediated by interleukin (IL)-6-induced T helper (TH) 17 cells, a TH17-directed anti-inflammatory therapy may be preferable to an IL-12-dependent TH1 inhibition in order to avoid reactivation of latent infections. To assess, however, the risk of inhibition of IL-6-dependent TH17-mediated inflammation, we examined the TH17 immune response and the course of experimental TB in IL-6- and T-cell-specific gp130-deficient mice. Our study revealed that the absence of IL-6 or gp130 on T cells has only a minor effect on the development of antigen-specific TH1 and TH17 cells. Importantly, these gene-deficient mice were as capable as wild type mice to control mycobacterial infection. Together, in contrast to its key function for TH17 development in other inflammatory diseases, IL-6 plays an inferior role for the generation of TH17 immune responses during experimental TB.

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Evaluation of Moxifloxacin-Containing Regimens in Pathologically Distinct Murine Tuberculosis Models

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00105-15 ◽

2015 ◽

Vol 59 (7) ◽

pp. 4026-4030 ◽

Cited By ~ 22

Author(s):

Si-Yang Li ◽

Scott M. Irwin ◽

Paul J. Converse ◽

Khisi E. Mdluli ◽

Anne J. Lenaerts ◽

...

Keyword(s):

Mouse Strain ◽

Predictive Accuracy ◽

Term Treatment ◽

Mouse Strains ◽

Disappointing Result ◽

Similar Treatment ◽

Infection Models ◽

Long Term Treatment ◽

Aerosol Infection

ABSTRACTIn the recently concluded REMox-TB trial, two 4-month moxifloxacin-containing regimens did not meet the criteria for noninferiority compared to the current 6-month first-line regimen to treat tuberculosis (TB). Despite the disappointing result, this phase 3 clinical trial provides a rare opportunity to gauge the predictive accuracy of the nonclinical models used to support regimen development. In parallel with the REMox-TB trial, we compared the efficacy of the same three regimens against chronic TB infection in the commonly used BALB/c mouse strain and in C3HeB/FeJ mice, which have attracted recent interest as a nonclinical efficacy model because they develop caseous lung lesions which may better resemble human TB. In long-term treatment experiments at two institutions, using low-dose aerosol infection models with 6- to 8-week incubation periods in both mouse strains, control mice received rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE), and test mice received the same regimen with moxifloxacin replacing isoniazid (RMZE) or ethambutol (RHZM). Outcome measures were lung CFU counts during treatment and relapse after various durations of treatment. At both institutions and in both mouse strains, RMZE and RHZM reduced by approximately 1 month and 0 to 1 month, respectively, the treatment duration needed to produce the same relapse rate as RHZE. These results demonstrating generally similar treatment-shortening effects of the moxifloxacin-containing regimens in each mouse strain, with effect sizes consistent with the REMox-TB trial results, reinforce the predictive value of murine models for TB regimen development.

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Individual Mycobacterium tuberculosis Resuscitation-Promoting Factor Homologues Are Dispensable for Growth In Vitro and In Vivo

Infection and Immunity ◽

10.1128/iai.72.1.515-526.2004 ◽

2004 ◽

Vol 72 (1) ◽

pp. 515-526 ◽

Cited By ~ 84

Author(s):

JoAnn M. Tufariello ◽

William R. Jacobs, ◽

John Chan

Keyword(s):

Mycobacterium Tuberculosis ◽

Stationary Phase ◽

Essential Gene ◽

Micrococcus Luteus ◽

Expression Patterns ◽

Active Growth ◽

Prolonged Incubation ◽

Aerosol Infection

ABSTRACT Mycobacterium tuberculosis possesses five genes with significant homology to the resuscitation-promoting factor (Rpf) of Micrococcus luteus. The M. luteus Rpf is a secreted ∼16-kDa protein which restores active growth to cultures of M. luteus rendered dormant by prolonged incubation in stationary phase. More recently, the Rpf-like proteins of M. tuberculosis have been shown to stimulate the growth of extended-stationary-phase cultures of Mycobacterium bovis BCG. These data suggest that the Rpf proteins can influence the growth of mycobacteria; however, the studies do not demonstrate specific functions for the various members of this protein family, nor do they assess the function of M. tuberculosis Rpf homologues in vivo. To address these questions, we have disrupted each of the five rpf-like genes in M. tuberculosis Erdman, and analyzed the mutants for their growth in vitro and in vivo. In contrast to M. luteus, for which rpf is an essential gene, we find that all of the M. tuberculosis rpf deletion mutant strains are viable; in addition, all show growth kinetics similar to Erdman wild type both in vitro and in mouse organs following aerosol infection. Analysis of rpf expression in M. tuberculosis cultures from early log phase through late stationary phase indicates that expression of the rpf-like genes is growth phase-dependent, and that the expression patterns of the five M. tuberculosis rpf genes, while overlapping to various degrees, are not uniform. We also provide evidence that mycobacterial rpf genes are expressed in vivo in the lungs of mice acutely infected with virulent M. tuberculosis.

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Efficacy and immunogenicity of different BCG doses in BALB/c and CB6F1 mice when challenged with H37Rv or Beijing HN878

10.1101/2020.10.21.349373 ◽

2020 ◽

Author(s):

Bhagwati Khatri ◽

James Keeble ◽

Belinda Dagg ◽

Daryan A. Kaveh ◽

Philip J. Hogarth ◽

...

Keyword(s):

Body Weight ◽

Laboratory Strain ◽

Bacterial Burden ◽

Significant Protection ◽

Bacille Calmette Guerin ◽

Human Dose ◽

Body Weight Index ◽

Aerosol Infection ◽

Immunological Evaluation ◽

Strain H37rv

AbstractIn this study, 2 strains of mice (BALB/c and CB6F1) were vaccinated with a range of Bacille Calmette-Guérin (BCG) Danish doses from 3×105 to 30 CFU/mouse, followed by either immunogenicity evaluation or aerosol infection with Mycobacterium tuberculosis (a laboratory strain H37Rv or West-Beijing HN878 strain). The results indicated that both strains of mice when infected with HN878 exhibited significant protection in their lungs with BCG doses at 3×105 – 3000 CFU (BALB/c) and 3×105-300 CFU (CB6F1). Whereas, both strains of mice when infected with H37Rv, significant protection was seen in BCG doses at 3×105 - 300 CFU. Immunological evaluation revealed interesting results; i) both strains of mice demonstrated a significant increase in the frequencies of BCG-specific IFNγ+ IL2+ TNFα+ CD4 T cells in the BCG doses at 3×105 – 3000 CFU (BALB/c) and 3×105 - 300 CFU (CB6F1); ii) secretion of IL2 and IFNγ were correlated with the bacterial burden in the lungs of HN878 infected CB6F1 mice. The study demonstrated a BCG dose at 3000 CFU (an equivalent single human dose in the mice by body weight index) is protective in both strains of mice and the use of a virulent clinical isolate in testing new tuberculosis vaccine/advancing research is recommended.

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Characterization of a Lipopolysaccharide-Targeted Monoclonal Antibody and Its Variable Fragments as Candidates for Prophylaxis against the Obligate Intracellular Bacterial Pathogen Coxiella burnetii

Infection and Immunity ◽

10.1128/iai.01695-14 ◽

2014 ◽

Vol 82 (11) ◽

pp. 4530-4541 ◽

Cited By ~ 6

Author(s):

Ying Peng ◽

Laura Schoenlaub ◽

Alexandra Elliott ◽

William J. Mitchell ◽

Guoquan Zhang

Keyword(s):

Monoclonal Antibody ◽

Coxiella Burnetii ◽

Natural Infection ◽

Bacterial Pathogen ◽

Passive Transfer ◽

Single Chain Variable Fragment ◽

Single Chain ◽

Fab Fragment ◽

Content Type ◽

Aerosol Infection

ABSTRACTOur previous study demonstrated that treatment ofCoxiella burnetiiwith the phase I lipopolysaccharide (PI-LPS)-targeted monoclonal antibody (MAb) 1E4 significantly inhibitedC. burnetiiinfection in mice, suggesting that 1E4 is a protective MAb. To determine whether passive transfer of antibodies (Abs) can provide protection againstC. burnetiinatural infection, we examined if passive transfer of 1E4 would protect SCID mice againstC. burnetiiaerosol infection. The results indicated that 1E4 conferred significant protection against aerosolizedC. burnetii, suggesting that 1E4 may be useful for preventingC. burnetiinatural infection. To further understand the mechanisms of 1E4-mediated protection and to test the possibility of using humanized 1E4 to preventC. burnetiiinfection, we examined whether the Fab fragment of 1E4 (Fab1E4), a recombinant murine single-chain variable fragment (muscFv1E4), and a humanized single-chain variable fragment (huscFv1E4) retained the ability of 1E4 to inhibitC. burnetiiinfection. The results indicated that Fab1E4, muscFv1E4, and huscFv1E4 were able to inhibitC. burnetiiinfection in mice but that their ability to inhibitC. burnetiiinfection was lower than that of 1E4. In addition, treatment ofC. burnetiiwith Fab1E4, muscFv1E4, or huscFv1E4 can blockC. burnetiiinfection of macrophages. Interestingly, treatment ofC. burnetiiwith huscFv1E4 can significantly reduceC. burnetiiinfectivity in human macrophages. This report provides the first evidence to demonstrate that the humanized variable fragments of an LPS-specific MAb can neutralizeC. burnetiiinfection and appears to be a promising step toward the potential use of a humanized MAb as emergency prophylaxis againstC. burnetiiexposure.

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A schlieren optical study of the human cough with and without wearing masks for aerosol infection control

Journal of The Royal Society Interface ◽

10.1098/rsif.2009.0295.focus ◽

2009 ◽

Vol 6 (suppl_6) ◽

Cited By ~ 72

Author(s):

Julian W. Tang ◽

Thomas J. Liebner ◽

Brent A. Craven ◽

Gary S. Settles

Keyword(s):

High Speed ◽

Fluid Dynamic ◽

Human Subjects ◽

Tracer Gas ◽

Airborne Infection ◽

Dynamic Mechanisms ◽

Human Volunteers ◽

Natural Mechanism ◽

Time Changes ◽

Aerosol Infection

Various infectious agents are known to be transmitted naturally via respiratory aerosols produced by infected patients. Such aerosols may be produced during normal activities by breathing, talking, coughing and sneezing. The schlieren optical method, previously applied mostly in engineering and physics, can be effectively used here to visualize airflows around human subjects in such indoor situations, non-intrusively and without the need for either tracer gas or airborne particles. It accomplishes this by rendering visible the optical phase gradients owing to real-time changes in air temperature. In this study, schlieren video records are obtained of human volunteers coughing with and without wearing standard surgical and N95 masks. The object is to characterize the exhaled airflows and evaluate the effect of these commonly used masks on the fluid-dynamic mechanisms that spread infection by coughing. Further, a high-speed schlieren video of a single cough is analysed by a computerized method of tracking individual turbulent eddies, demonstrating the non-intrusive velocimetry of the expelled airflow. Results show that human coughing projects a rapid turbulent jet into the surrounding air, but that wearing a surgical or N95 mask thwarts this natural mechanism of transmitting airborne infection, either by blocking the formation of the jet (N95 mask), or by redirecting it in a less harmful direction (surgical mask).

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