Potentials and challenges of launching the pilot phase of Hong Kong Genome Project

Genomic medicine and precision medicine initiatives have taken centre stage in scientific, clinical, as well as health economics and utility research on the global scene for the past decade. It is clear the important role genomic advancement has played in enhancing diagnostic rate, streamlining personalised treatment, and improving efficacy of the overall clinical management of undiagnosed, rare, and common diseases for humankind. The Hong Kong Genome Institute (HKGI) was established in May 2020 within the Food and Health Bureau, Hong Kong Special Administrative Region, to integrate genomic medicine into mainstream healthcare. The main goals of setting up HKGI are to (1) improve the diagnostic rate and future care for individuals affected by undiagnosed diseases and hereditary cancers using whole genome sequencing; (2) advance research in genomic science; (3) nurture talents in genomic medicine; and (4) enhance public genomic literacy and overall engagement through the launching of the Hong Kong Genome Project (HKGP). In this paper, we review the current landscape and specific challenges encountered during the construction of the infrastructure and implementation of the pilot phase of HKGP. Through reviewing what has been achieved and established to date, and the potentials and prospects that have emerged in the process, this paper will provide insights into planning the main phase of HKGP, and considerations for our international counterparts when building similar projects

Mp1p Is a Virulence Factor in <i>Talaromyces (Penicillium) marneffei</i>

<div><p>Background</p><p><i>Talaromyces marneffei</i> is an opportunistic dimorphic fungus prevalent in Southeast Asia. We previously demonstrated that Mp1p is an immunogenic surface and secretory mannoprotein of <i>T</i>. <i>marneffei</i>. Since Mp1p is a surface protein that can generate protective immunity, we hypothesized that Mp1p and/or its homologs are virulence factors.</p><p>Methodology/Principal Findings</p><p>We examined the pathogenic roles of Mp1p and its homologs in a mouse model. All mice died 21 and 30 days after challenge with wild-type <i>T</i>. <i>marneffei</i> PM1 and <i>MP1</i> complemented mutant respectively. None of the mice died 60 days after challenge with <i>MP1</i> knockout mutant (P<0.0001). Seventy percent of mice died 60 days after challenge with <i>MP1</i> knockdown mutant (P<0.0001). All mice died after challenge with <i>MPLP1</i> to <i>MPLP13</i> knockdown mutants, suggesting that only Mp1p plays a significant role in virulence. The mean fungal loads of PM1 and <i>MP1</i> complemented mutant in the liver, lung, kidney and spleen were significantly higher than those of the <i>MP1</i> knockout mutant. Similarly, the mean load of PM1 in the liver, lung and spleen were significantly higher than that of the <i>MP1</i> knockdown mutant. Histopathological studies showed an abundance of yeast in the kidney, spleen, liver and lung with more marked hepatic and splenic necrosis in mice challenged with PM1 compared to <i>MP1</i> knockout and <i>MP1</i> knockdown mutants. Likewise, a higher abundance of yeast was observed in the liver and spleen of mice challenged with <i>MP1</i> complemented mutant compared to <i>MP1</i> knockout mutant. PM1 and <i>MP1</i> complemented mutant survived significantly better than <i>MP1</i> knockout mutant in macrophages at 48 hours (P<0.01) post-infection. The mean fungal counts of <i>Pichia pastoris</i> GS115-<i>MP1</i> in the liver (P<0.001) and spleen (P<0.05) of mice were significantly higher than those of GS115 at 24 hours post-challenge.</p><p>Conclusions/Significance</p><p>Mp1p is a key virulence factor of <i>T</i>. <i>marneffei</i>. Mp1p mediates virulence by improving the survival of <i>T</i>. <i>marneffei</i> in macrophages.</p></div

Phylogenetic analysis of the putative LBD of Mp1p homologs in <i>T</i>. <i>marneffei</i> and orthologs in other fungi.

<p>Homologs of Mp1p in <i>T</i>. <i>marneffei</i> are shown in bold. The tree was constructed by maximum likelihood method with bootstrap values calculated from 1,000 trees and rooted on midpoint. The scale bar indicates the branch lengths that correspond to 0.5 substitutions per site as indicated. Names and accession numbers are given as cited in the GenBank database.</p

Mp1p is a virulence factor of <i>T</i>. <i>marneffei</i>.

<p>(A) Survival curves of Balb/c mice challenged with <i>T</i>. <i>marneffei</i> PM1, <i>MP1</i> knockout mutant, <i>MP1</i> complemented mutant and knockdown mutants (***P<0.0001). (B) Mean fungal burden in spleen, kidney, liver and lung of mice challenged with <i>T</i>. <i>marneffei</i> PM1, <i>MP1</i> knockout mutant, <i>MP1</i> complemented mutant and <i>MP1</i> knockdown mutant at day 12 post-challenge (***P<0.001, **P<0.01, *P<0.05). Error bars represent standard deviations. (C) Histopathological examination of PAS stained internal organs of mice at day 12 post-challenge. <i>T</i>. <i>marneffei</i> yeast cells are shown in black arrows and tissue necrosis in blue arrows.</p

Characteristics of Mp1p homologs in <i>T</i>. <i>marneffei</i>.

<p>Characteristics of Mp1p homologs in <i>T</i>. <i>marneffei</i>.</p

Fungal strains used in this study

<p>Fungal strains used in this study</p

Mp1p enhances <i>T</i>. <i>marneffei</i> survival in macrophages.

<p>Intracellular survival of <i>T</i>. <i>marneffei</i> PM1, <i>MP1</i> knockout mutant, <i>MP1</i> complemented mutant and <i>MP1</i> knockdown mutant in murine macrophages at 2, 8, 16, 24 and 48 hours post-inoculation (**P<0.01). Error bars represent standard deviations.</p