Vitamin D, innate immunity and outcomes in community acquired pneumonia

We investigated the associations between vitamin D status, the antimicrobial peptides cathelicidin and beta defensin-2 and outcomes in community acquired pneumonia. In hospitalised patients with community acquired pneumonia, vitamin D deficiency but not antimicrobial peptide levels were associated with increased 30-day mortality. Vitamin D was not associated with levels of the antimicrobial peptide cathelicidin or beta defensin-2

Whole genome sequencing of Mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans

Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10⁻¹⁰ mutations/bp/generation for recently transmitted tuberculosis and 7.3X10⁻¹¹ mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10⁻¹¹ mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques

Complete genome sequence of a New Zealand Mycobacterium tuberculosis strain responsible for ongoing transmission over the past 30 years.

We report here the complete genome sequence of Mycobacterium tuberculosis strain Colonial S-type 1 (CS1), which has been responsible for ongoing outbreaks of tuberculosis in New Zealand over the past 30 years. CS1 appears to be highly transmissible, with greater rates of progression to active disease, compared to other circulating M. tuberculosis strains; therefore, comparison of its genomic content is of interest

Epidemiological relationships among 11 New Zealand <i>M. tuberculosis</i> cases.

<p>Chronological representation of different subjects in a New Zealand TB outbreak. Each square represent a subject at the time of the TB diagnosis. Broken lines represent known close direct contact with the initial index case “X” during X's period of infectiousness. Solid lines show assumed connections between a case of presumed reactivation (C1 to C2) and a case of potential child-parent transmission (A to T).</p

Mutation versus replication rates during the latency period.

<p>To evaluate if the mutation rate was different in early versus late period of latent-reactivated disease, we estimated the mutation rate (calculated as untis of mutation/bp/generation) for isolates with reactivation of TB for the latent and reactivated years. <b>Panel A</b>: A schematic representation for the evaluation of the rate of mutation in the latency period. The mutation rate of the recent activated TB (strains C1 and E) was subtracted from the late activated TB (strains O and S).<b>Panel B</b>: The mutation rate for the latent period was calculated using the difference between the number of mutations for the early reactivation phase and the late reactivated phase. The result was divided by the genome size multiplied by the number of generations for O and S combined in the presumed latent period. All these calculations implicitly assume a homogeneous mutation rate across the genome and over time and when combining activation groups, across isolates. Analyses were performed using PROC GENMOD in SAS 9.2 (SAS Institute Inc, Cary, NC). Graphics were generated using R 2.12.2 (R Foundation for Statistical Computing).</p

Single nucleotide polymorphisms identified in sequenced isolates.

1<p>reference genome.</p

In vivo mutation rates in <i>M. tuberculosis</i> strains for generation times ranging from 18 to 240 hours.

<p>The mutation rate for each of the <i>M. tuberculosis</i> isolates was estimated using equation (1) in Ford <i>et al</i>, and calculated as untis of mutation/bp/generation <b>Panel A</b>: The mutation rate for each <i>M. tuberculosis</i> isolate in the study. Isolate C1 and E are from recent infection while strains O and S from reactivation after a prolonged period of latency. The yellow areas represent 95% confidence intervals. <b>Panel B</b>: Isolates with recent infection (E and C1) and reactivation after prolonged latency (O and S) were combined to obtain overall estimates of mutation rates of recent and latent-reactivated disease. The yellow areas represent 95% confidence intervals.</p

Evolutionary history of <i>M. tuberculosis</i> strains isolated from a cluster of cases in New Zealand.

<p>Relationships were inferred by examining parsimony and nonparsimony informative single nucleotide polymorphisms (SNPs). <b>Panel A</b>: parallelogram of network analysis using 34 SNPs including five homoplastic SNPs. <b>Panel B</b>: Evolutionary tree using the same 34 SNPs as in A rooted on <i>M. tuberculosis</i> H₃₇Rv analyzed using Neighbor-joining method. Panel C. Evolutionary tree examining 29 nonparsimony SNPs using the Neighbor-joining method. The evolutionary distances represent the number of SNP differences per strain.</p

Number of single nucleotide polymorphisms differences between each strain.

<p>Number of single nucleotide polymorphisms differences between each strain.</p