Predominance of Ancestral Lineages of Mycobacterium tuberculosis in India

Molecular epidemiologic findings suggest an ancient focus of TB

Angé (Loir-et-Cher) : un site moustérien à influences multiples

FdA – Publicaties zonder aanstelling Universiteit Leide

Time-resolved predissociation of the vibrationless level of the B state of CH3I

The predissociation dynamics of the vibrationless level of the first Rydberg state 6s (B 2E) state of CH3I has been studied by femtosecond-resolved velocity map imaging of both the CH3 and I photofragments. The kinetic energy distributions of the two fragments have been recorded as a function of the pump-probe delay, and as a function of excitation within the umbrella and stretching vibrational modes of the CH3 fragment. These observations are made by using (2+1) Resonant Enhanced MultiPhoton Ionization (REMPI) via the 3pz 2A2" state of CH3 to detect specific vibrational levels of CH3. The vibrational branching fractions of the CH3 are recovered by using the individual vibrationally state-selected CH3 distributions to fit the kinetic energy distribution obtained by using nonresonant multiphoton ionization of either the I or CH3 fragment. The angular distributions and rise times of the two fragments differ significantly. These observations can be rationalized through a consideration of the alignment of the CH3 fragment and the effect of this alignment on its detection efficiency. Two extra dissociation channels are detected: one associated with Rydberg states near 9.2 eV that were observed previously in photoelectron studies, and one associated with photodissociation of the parent cation around 15 eV.Comment: submitted Physical Chemistry Chemical Physics (2011

Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis

Accumulating evidence from experimental animal models suggests that antibodies play a protective role against tuberculosis (TB). However, little is known about the antibodies generated upon Mycobacterium tuberculosis (MTB) exposure in humans. Here, we performed a molecular and functional characterization of the human B‐cell response to MTB by generating recombinant monoclonal antibodies from single isolated B cells of untreated adult patients with acute pulmonary TB and from MTB‐exposed healthcare workers. The data suggest that the acute plasmablast response to MTB originates from reactivated memory B cells and indicates a mucosal origin. Through functional analyses, we identified MTB inhibitory antibodies against mycobacterial antigens including virulence factors that play important roles in host cell infection. The inhibitory activity of anti‐MTB antibodies was directly linked to their isotype. Monoclonal as well as purified serum IgA antibodies showed MTB blocking activity independently of Fc alpha receptor expression, whereas IgG antibodies promoted the host cell infection. Together, the data provide molecular insights into the human antibody response to MTB and may thereby facilitate the design of protective vaccination strategies

Live Attenuated B. pertussis as a Single-Dose Nasal Vaccine against Whooping Cough

Pertussis is still among the principal causes of death worldwide, and its incidence is increasing even in countries with high vaccine coverage. Although all age groups are susceptible, it is most severe in infants too young to be protected by currently available vaccines. To induce strong protective immunity in neonates, we have developed BPZE1, a live attenuated Bordetella pertussis strain to be given as a single-dose nasal vaccine in early life. BPZE1 was developed by the genetic inactivation or removal of three major toxins. In mice, BPZE1 was highly attenuated, yet able to colonize the respiratory tract and to induce strong protective immunity after a single nasal administration. Protection against B. pertussis was comparable to that induced by two injections of acellular vaccine (aPV) in adult mice, but was significantly better than two administrations of aPV in infant mice. Moreover, BPZE1 protected against Bordetella parapertussis infection, whereas aPV did not. BPZE1 is thus an attractive vaccine candidate to protect against whooping cough by nasal, needle-free administration early in life, possibly at birth

Distinct virulence ranges for infection of mice by Bordetella pertussis revealed by engineering of the sensor-kinase BvgS

The whooping cough agent Bordetella pertussis coordinately regulates the expression of its virulence factors with the two-component system BvgAS. In laboratory conditions, specific chemical modulators are used to trigger phenotypic modulation of B. pertussis from its default virulent Bvg+ phase to avirulent Bvg- or intermediate Bvgi phases, in which no virulence factors or only a subset of them are produced, respectively. Whether phenotypic modulation occurs in the host remains unknown. In this work, recombinant B. pertussis strains harboring BvgS variants were tested in a mouse model of infection and analyzed using transcriptomic approaches. Recombinant BP-BvgΔ65, which is in the Bvgi phase by default and can be up-modulated to the Bvg+ phase in vitro, could colonize the mouse nose but was rapidly cleared from the lungs, while Bvg+-phase strains colonized both organs for up to four weeks. These results indicated that phenotypic modulation, which might have restored the full virulence capability of BP-BvgΔ65, does not occur in mice or is temporally or spatially restricted and has no effect in those conditions. Transcriptomic analyses of this and other recombinant Bvgi and Bvg+-phase strains revealed that two distinct ranges of virulence gene expression allow colonization of the mouse nose and lungs, respectively. We also showed that a recombinant strain expressing moderately lower levels of the virulence genes than its wild type parent was as efficient at colonizing both organs. Altogether, genetic modifications of BvgS generate a range of phenotypic phases, which are useful tools to decipher host-pathogen interactions

Impact of HIV Infection on the Recurrence of Tuberculosis in South India

Background. There is limited information on the relative proportion of reactivation and reinfection at the time of recurrence among human immunodeficiency virus (HIV)-infected and HIV-uninfected patients who are successfully treated for tuberculosis infection in India. Methods. HIV-infected and HIV-uninfected patients with sputum culture-positive pulmonary tuberculosis were treated with short-course regimens and followed up for 36 months at the Tuberculosis Research Centre, South India. Bacteriologic recurrences were documented, and typing of strains was performed using 3 different genotypic techniques: restriction fragment length polymorphism (RFLP) by IS6110, spoligotyping, and mycobacterial interspersed repeat unit (MIRU)-variable number tandem repeat (VNTR). DNA fingerprints of paired Mycobacterium tuberculosis isolates (baseline and recurrence) were compared. Results. Among 44 HIV-infected and 30 HIV-uninfected patients with recurrent tuberculosis during the period July 1999 to October 2005, 25 and 23 paired isolates, respectively, were typed using all 3 methods. Recurrence was due to exogenous reinfection in 88% of HIV-infected and 9% of HIV-uninfected patients (P < .05). Among recurrent isolates, the HIV-infected patients showed more clustering, as well as a higher proportion of drug resistance, including multidrug resistance. Conclusions. In India, a tuberculosis-endemic country, most recurrences after successful treatment of tuberculosis are due to exogenous reinfection in HIV-infected persons and endogenous reactivation in HIV-uninfected persons. Strategies for prevention and treatment of tuberculosis infection must take these findings into consideration