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Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates PRKCA | mBio

[Open Access] [Received 22 December 2019; Accepted 2 January 2020; Published 4 February 2020]

ABSTRACT

Diarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and sub-Saharan Africa, where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long-term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, and yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh, namely, the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for length-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 (P = 3.73 × 10⁻⁸), an intronic SNP and expression quantitative trait locus (eQTL) of protein kinase C alpha (PRKCA). Each additional risk allele conferred 2.4 times the odds of Cryptosporidium-associated diarrhea in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation.

IMPORTANCE Globally, diarrhea remains one of the major causes of pediatric morbidity and mortality. The initial symptoms of diarrhea can often lead to long-term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here, we conducted a genetic study of susceptibility to symptomatic disease associated with Cryptosporidium infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase C alpha (PRKCA) associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism.

CIDRAP News Scan for Feb 06, 2020 | The Center for Infectious Disease Research and Policy at the University of Minnesota.

Ebola case in the DRC; Resistance genes in Chicago waterways.

One more Ebola case recorded in DRC.

According to the World Health Organization's (WHO's) online Ebola dashboard, a new case recorded today raises the outbreak total to 3,430 confirmed cases in the ongoing outbreak in the Democratic Republic of the Congo (DRC). The WHO also noted 123 probable cases, and 524 suspected cases still under investigation.

Since the outbreak in North Kivu and Ituri provinces began in August 2018, 2,247 people have died from Ebola virus disease (EVD).

Yesterday the DRC's Ebola technical committee (CMRE) said the single case reported yesterday was from Beni, the current hot spot for the virus. It also said a new fatality took place in the community in Beni, which raises the risk of further transmission of the deadly virus.

The CMRE also updated vaccine totals, with 9,924 people having received the Johnson & Johnson vaccine to date, and 287,652 having received Merck's rVSV-ZEBOV.
WHO Ebola dashboard
Feb 5 CMRE update

Study finds Chicago waterways harboring multidrug-resistance genes.

A pilot study conducted in Chicago has identified waterways as a potential source of community-acquired multidrug-resistant Enterobacteriaceae (MDR-Ent), researchers reported this week in Antimicrobial Agents and Chemotherapy.

Motivated by research showing a greater risk of community-acquired MDR-Ent infections in children in certain Chicago neighborhoods, mainly those in zip codes in close proximity to area waterways, a team that included researchers from Rush University Medical Center and Virginia Tech evaluated four Chicago waterways for MDR-Ent and associated antibiotic resistance genes (ARGs) using culture-based and cultivation-independent shotgun metagenomic sequencing approaches. Three of the waterways (A1 – A3) are labelled safe for "incidental contact recreation" (fishing and boating) and one (A4) is a non-recreational waterway that carries non-disinfected water.

Analysis of the shotgun metagenomic sequence data revealed the presence of 37 different ARGs derived from Enterobacteriaceae, including those conferring resistance to quinolones, beta-lactamases, polymyxins, and aminoglycosides. The greatest number and highest relative abundances of Ent-associated ARGs was found in samples from A4, and A3—which was in the same area but not hydraulically connected—had a similar ARG profile. Escherichia coli concentrations were also highest in A4 and A3, and the ARGs of clinical concern were most abundant in A4 and A3. Among the ARGs of clinical concern were MCR-1 (which confers resistance to colistin), Qnr and OqxA/B (quinolones), CTX-M and OXA (beta-lactams), and AAC (aminoglycosides).

Fifteen E coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates cultured from A2-A4 samples were found to harbor transmissible ARGs that were also found in clinical isolates from children in the region, and 60% of those isolates were resistant to three or more antibiotic classes.

"These results suggest the potential for mobility of ARGs of clinical concern in waterways located in a high-risk region for MDR-Ent infections in Chicago," the authors of the paper write. "Ent and ARG profiles were consistent with the hypothesized concerns that waterways are a source of community-acquired MDR-Ent."
Feb 3 Antimicrob Agents Chemother abstract

The Rapid Response Team Steering Africa’s Polio Fight | GPEI.

[06/02/2020]

Meet the experts who deploy at a moment's notice to fight outbreaks across the region.

A vaccine is administered to a child during a polio immunization campaign. ©WHO/AFRO

From a small prefabricated container where the walls host detailed maps and desks prop up computer screens beaming data, tables and graphics, the Rapid Response Team at the World Health Organization’s (WHO) Regional Office for Africa coordinate polio outbreak response. The team work across the continent, where 12 countries are battling the vaccine-derived strain of the virus.

Dr Ndoutabe Modjirom, a former Chadian university professor-turned WHO medical officer, coordinates the multi-agency team, which was formed in September 2019. It is composed of twenty experts in operations and vaccination management, epidemiology, logistics, and communications. They are drawn from the core partners of the Global Polio Eradication Initiative (GPEI): WHO, the United Nations Children’s Fund (UNICEF), Rotary International, the US Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, and Gavi, The Vaccine Alliance.

The team is mobilized whenever a new polio outbreak is confirmed in the African region.

The first 72 hours.

“Our work starts once the lab confirms that a sample collected from either the environment or a paralysed child is caused by a poliovirus. Every minute that passes after the lab confirmation means that the poliovirus is circulating and risks infecting more children,” says Dr Modjirom.

Within the first 72 hours, the Rapid Response Team deploys Team A. This team includes the GPEI Coordinator alongside an epidemiologist, an operations officer, a vaccine manager and a communicator for development. The team works closely with the health authorities in the affected country along with the relevant WHO and UNICEF country offices to prepare a risk assessment and outbreak response plan. The emergency response vaccination campaign, called ‘Round Zero’, starts within 14 days.

Team B takes over from Team A after the first eight weeks and continues the outbreak response activities.

According to standard operating procedures for responding to outbreaks, the polio programme must implement three rounds of high-quality vaccination campaigns in response to every outbreak. Parallel to vaccination, countries must intensify disease surveillance activities to detect new cases of acute flaccid paralysis, a clinical symptom of poliomyelitis.

“Priorities are constantly shifting for the Rapid Response Team,” says Dr Christopher Kamugisha, who has been working with WHO since 1998. He has been a member of the Rapid Response Team since its inception and like the rest of the team has been chasing new polio outbreaks across the region.

“In August I was in Somali Region in Ethiopia supporting the outbreak response, conducting the first vaccination campaign round. On the second day of the campaign, Dr Ndoutabe informed me that a new case was detected in Cheporoni in Ghana and asked me to go and provide technical support,” Dr Kamugisha recalls.

The Rapid Response Team gathers to discuss their next deployments. ©WHO/AFRO

Within 24 hours, he was on a plane to Accra through Addis.

“I arrived at noon the next day and went straight to support the national technical team in their preparations and risk assessment. I assisted with ensuring that their plans are in line with the international standard operating procedures set by the GPEI,” Dr Kamugisha says.

No cure for polio.

Polio is a viral disease, multiplying in the intestines and transmitted from person to person mainly through a faecal-oral route or, less frequently, through contaminated water or food.

While there is no cure for polio, the disease can be prevented through administration of a simple and effective vaccine. That is why efforts are underway across the country to rapidly boost immunity levels in children and protect them from polio paralysis.

Thanks to the efforts of the GPEI and country governments, no wild poliovirus has been detected anywhere in Africa since 2016. This stands in stark contrast to 1996, a year when wild poliovirus paralysed more than 75,000 children across every country on the continent.

In 2020, the central challenge for the African Region is overcoming outbreaks of circulating vaccine derived poliovirus. Vaccine-derived polioviruses are rare, but can affect unimmunized and under-immunized populations living in areas with inadequate sanitation and low levels of polio immunization.

Countries experiencing outbreaks of vaccine-derived poliovirus in Africa are Angola, Benin, Cameroon, Central African Republic, Chad, Côte d’Ivoire, Democratic Republic of the Congo, Ethiopia, Ghana, Nigeria, Togo and Zambia. Reasons these outbreaks have occurred include weak routine vaccination systems, vaccine hesitancy, difficulty accessing some locations and low-quality vaccination campaigns, which have made immunization of all children challenging.

In addition to the response activities, the Rapid Response Team work to build the capacity of health workers and decision makers in countries that are not experiencing polio outbreaks, training them to be ready to respond if virus is ever detected.

The team also aims to recruit more women with expertise in outbreak response. Achieving gender balance amongst personnel through a more equitable recruitment process forms part of the GPEI Gender Equality Strategy 2019 – 2023, which was launched in May 2019.

By supporting countries during outbreaks, and building health system resilience in vulnerable settings, the polio programme is working to establish a sustainable legacy that will improve health long after global eradication of the virus.

Related resources.

UNICEF-WHO Philippines: Polio Outbreak Situation Report #15 (6 February 2020) | World Health Organization, UN Children's Fund via ReliefWeb.

[06 Feb 2020]

Highlights.

• Since 27 January 2020, no new confirmed human case.

• Currently, there are 13 cases of cVDPV2, one case with cVDPV1; one case with VDPV1; and one case with immunodeficiency-related VDPV type 2 (iVDPV2).

• Third round of Sabayang Patak Kontra Polio mOPV2 started in Mindanao on 20 January targeting 3,102,973 children under 5. In the first 14 days of the campaign, 3,057,875 children under 5 were vaccinated.

• NCR on 27 January started its first mOPV rounds, and targets 1,404,517 children under 5. In the first 4 days of the campaign, 1,126,979 children under 5 were vaccinated (80.2%). The second round is planned for 24 February-8 March 2020.

• The first poliovirus Outbreak Response Assessment (OBRA) is planned from 8-14 February.

• Current polio outbreak resulted from persistently low routine immunization coverage, poor sanitation, and hygiene.

• Philippines is affected by both cVDPV1 and cVDPV2. cVDPV is considered a public health emergency of international concern (PHEIC).

Pakistan: Polio cases tally hits 2017 figure on 36th day of 2020 | DAWN.

[February 06, 2020] Ikram Junaidi writes:

ISLAMABAD: Another polio case reported from Sindh was confirmed on Wednesday.

With this addition, the number of polio cases detected this year from across the country has reached eight. Of them, four were reported from Khyber Pakhtunkhwa.

The latest victim is a 40-month-old girl hailing from Jaml union council of Kashmore district’s Yang­wani tehsil, said an official of the National Institute of Health, Islamabad, on condition of anonymity as he was not authorised to speak on record.

“Both legs of the child have been paralysed and socioeconomic status of child has been declared poor. Her father is a farmer. It has been decided to start a polio campaign in the area from Feb 17,” he said.

So far this year, eight cases have been detected, including three in Sindh and one in Balochistan, across the country. In all, 144 cases were reported last year, 12 in 2018, and eight in 2017.

Polio is a highly infectious disease caused by poliovirus mainly affecting children under the age of five. It invades the nervous system and can cause paralysis or even death. While there is no cure for polio, vaccination is the most effective way to protect children from this crippling disease. Each time a child aged less than five is vaccinated, their protection against the virus is increased. Repeated immunisations have protected millions of children from polio, allowing almost all countries to become polio free.

Pakistan, which is one of the two countries in the world where polio cases are still being reported, remains under a polio-linked travel restriction recommended by the World Health Organisation since 2014 due to which every person travelling abroad has to carry a polio vaccination certificate.

Ghana: Allow your children to be immunised against polio - Biakoye District Health Director urges | myjoyonline.com.

[05-02-2020] Fred Quame Asare writes:

The Biakoye District Health Directorate is hoping to attain a 95% coverage in a 4-day Round Two Polio Vaccination campaign in the Oti Region.

About 16,115 children under 5 years are expected to receive a dose of the Polio Vaccine (mOPV) in the district during the campaign which commenced on 5th February and ends on 8th February 2020. 

However, some parents ignorantly prevent their children from receiving the vaccine, hereby affecting the success of the campaign.

Due to this, the Biakoye District Director of the Ghana Health Services, Rita Wurapah-Abudey is pleading with such parents to allow their children to be vaccinated to make them immune against the poliovirus.

She detailed that the polio vaccine has been tried, tested and approved over the years, hence would have no side effect(s) on the health of the children. 

”Few mothers are refusing their children to receive the vaccine. The vaccine has been tested and tried and it has proven to very effective and efficient, that is why it is being administered.”

”So I am encouraging every parent to allow their children to receive the vaccine”, she stressed.

Madam Wurapah-Abudey stated that 62 teams made up of 178 personnel have been deployed to undertake the exercise in the district which had demarcated into 6 sub-districts ”for easy access”. 

”18 supervisors, district and sub-district coordinators, and 7 vaccine accountability monitors are also on the field”, she added. 

The Biakoye District Director further stated that the district health directorate has put adequate measures to extend the vaccination exercise to all hard to reach communities to achieve the targeted 95% coverage. 

”Because of the population and terrain in the 38 overbank communities, we have deployed a team to go and stay there. They will spend about 7 days there working to ensure all children in the age bracket receive the vaccine.”

The mass reactive vaccination exercise was necessitated by the detection of polio cases in the Nkwanta North and Krachi Nchumuru Districts. 

This is in line with the World Health Organization’s (WHO’s) recommendation for 3 rounds of oral polio vaccine to be administered to eligible children in a mass vaccination campaign in the affected region, to prevent the possible re-emergence of the child killer disease in Ghana.

Pakistan: Govt to regulate border movement to eradicate polio | The Express Tribune.

[February 6, 2020] Rizwan Ghilzai writes:

ISLAMABAD: Prime Minister Imran Khan on Wednesday said that the government was taking special measures to regulate the movement from Pakistan-Afghanistan border in order to halt the spread of polio virus.

He expressed this on Wednesday in a meeting with a high level delegation of Rotary International led by its President Holger Knaack discussing current situation of polio in Pakistan and measures taken by the government to eradicate the paralysing disease from the country.

The prime minister paid high regard to efforts of international organisations especially Rotary International working to eradicate polio from Pakistan.

“Eradication of polio is the foremost priority of the government and the whole nation is on one page for the cause,” said the prime minister pledging full support to the organisation in its operations.

Two more polio cases detected in DG Khan

The prime minister expressed his determination to utilise all resources for the eradication of the paralysing disease from the country.

Special Assistant to Prime Minister on National Health Services Dr Zafar Mirza also attended the meeting.

Briefing the members about measures taken by Imran-led government to eradicate polio, Mirza said, “More than 0.1 million security officials and 0.25 million polio workers took part in the current polio campaign to administer drops to 40 million children under the age of five years.”

The delegation hailed efforts of the government to eradicate polio.

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