Hunting Viruses: Meet Alyson Kelvin

By Dr Alyson Kelvin

Soapbox Science Halifax is coming up quickly. In my previous post, I introduced myself as a virologist, and I discussed the purpose of Soapbox Science and the importance of supporting women in STEM. As I look forward to the event, I am preparing my presentation and activities for the day, focusing on my research and interests in virology. I am ready to discuss with you the basics of viruses, my work on developing vaccines at the Canadian Centre for Vaccinology (CCfV), and HOW I Hunt Viruses….

 

A Bit About Viruses

Picture 1: credit Don Stoltz

Viruses are considered intracellular parasites since viruses are only able to be active and reproduce once inside a cell (Picture 1). Scientists often debate whether or not viruses are living because alone, they are not active and instead require the machinery of a living cell to function. Ranging in size from 20 to 400 nanometers (typically 20-110), viruses are microscopic and can’t be seen by the naked eye. They exist all around us, including in the air, water, and dirt, as well as inside the cells of bacteria and animals.  Although viruses are typically associated with disease, viruses don’t always cause illness. In some cases, viruses are beneficial, such as the oncolytic viruses that destroy cancer cells, and bacteriopahges – viruses of bacteria – that can be employed to treat antibiotic-resistant bacterial infections. To combat disease-causing viruses, our human bodies as well as other multi- and single-cell organisms have developed defense systems known as immune systems. With respect to human and animal disease, we have invented vaccines and antivirals to extend our protection during infection when our natural immune defense systems are unable to cover a particular deleterious virus. My work and the work of my colleagues at CCfV and IWK is focused on improving vaccines, evaluating existing vaccines, and — importantly — developing vaccines for the new and threatening viruses that are emerging, such as Ebola and Zika.

 

Viruses are categorized by family and each virus family is defined by the virus’s genetic material which encodes the proteins needed for the virus to function.  Unlike animals and plants which only have DNA as the genetic hereditary material, the genome of viruses can either be composed of DNA or RNA. Beyond this basic dichotomy of DNA or RNA, the viral genome is classified by its structure and order.  This can be double-stranded, single-stranded, positive sense, negative sense, or retroviral meaning moving from RNA to DNA and the structure may be linear, circular, segmented, or gapped.

 

picture 2: credit Don Stoltz

The complete virus particle is referred to as the VIRION. The virion contains genetic material and proteins responsible for infecting cells and moving the viral genome between cells.  The viral surface and structural proteins typically give each virus a shape characteristic of its virus type. The virion can take on various shapes and sizes including, spherical, geometric, and cylindrical (Picture 2). The nucleic acid genome of the virus is protected by a protein coat. Some viruses also have an envelope that is typically formed from a host cell membrane during virus egress (i.e., when virus escapes from a host cell). Influenza viruses, for example, are enveloped viruses of the Orthomyxovirus family that contain receptors creating an overall spherical structure covered in nobs or lollipop-shaped proteins. Differing is the Ebola virus, a member of the Filovirus family. The Ebola virus is long and tube-like or filamentous in structure, inspiring the Filovirus family name.

 

How does one become infected with a virus? Understanding how viruses spread is inherently important to knowing how to keep from becoming infected. The spread of viruses between hosts – from one infected host to a susceptible one – is called transmission. There are several different modes of transmission for viruses. Transmission can be grouped as either being Direct or INDIRECT. Direct transmission occurs by direct contact with an infected source either by touching, kissing, sexual intercourse, or droplet spray. Bloodborne viruses are viruses present in an infected host’s blood; they can be spread to a susceptible host through direct contact. Examples of bloodborne transmitted viruses are HIV and Hepatitis B. Vertical transmission is another type of direct transmission and occurs when a virus is passed from an infected mother to her infant either during pregnancy, childbirth, or breastfeeding.

 

Conversely, viruses transmitted by indirect means use a vehicle to move the virus from one host to another.  Indirect spread may occur through 1.) the air; 2.) contact of contaminated non-living objects (such as touching a door knob that was previously used by sick person); or 3.) living vectors.   Respiratory viruses such as influenza can be spread through the air when an infected host coughs, sneezes, or breathes. The release of virus particles allows the virus to move in the air and be inhaled into the respiratory tract of a susceptible host. Viruses also may gain access to uninfected hosts through oral transmission. Oral transmission occurs when viruses contaminating food and water are ingested, leading to infection. Examples of viruses using oral transmission include rotavirus, enterovirus, and coxsackievirus, which is the agent for hand-foot-and-mouth disease.

 

Vectorborne transmission is a type of indirect transmission that is responsible for the emergence of several novel viruses threatening the health of humans. Vectorborne transmission is the transmission of a virus through the medium of an insect such as a mosquito, tick, or fly. Specifically, viruses transmitted by an insect are referred to as an arthropod-borne virus or arbovirus. ZIKA virus and Dengue virus are examples of viruses spread by insects, specifically by the bite of a mosquito. Through the bloodmeal of a mosquito or tick, viruses can be picked up from a reservoir animal species, such as monkeys, and during a subsequent feeding on humans, the virus may spread from the now virus-carrying insect to a susceptible uninfected human.  The U.S. CDC has recently reported that infectious diseases spread by mosquitos and ticks are on the rise, reinforcing the importance of studying insect-transmitted viruses.

 

Emerging viruses are the unknown threat to human and animals. Over the past 15 years there have been several examples of emerging infectious diseases that have significantly affected human health making global headlines in newspapers, on TV, and on the internet.  Examples include the H1N1 influenza pandemic in 2009, the emergence of SARS in 2003 in the Guangdong, and the most recent ZIKV outbreak in the Americas. These viruses have significant impact on humans because humans are naïve to these pathogens having no previous exposure or immunity.

 

 

Emerging Viruses and Virus Hunting

 

My main interests are investigating how emerging viruses and pathogens move from their animal reservoir to infect humans and cause disease. Following a virus from its emergence to human infection and illness is Virus Hunting. Most of the viruses that infect and cause disease in humans today originated in animals such as birds, bats, or non-human primates. The emergence event where a virus transmits from an animal and infects a human is called “zoonosis” or, colloquially, as “spillover” between species. My interest and the public health importance of understanding emerging pathogens has led me to investigate viruses such as influenza, Zika, Chikungunya, and SARS. It is important to be continually researching how emerging viruses are spilling over into humans, who may be susceptible to developing severe disease, and how we can prevent spillover.

 

Zika virus emerged in Brazil in 2015 and was a cause of public health concern as Zika cases were correlated with an increase in infants born with microcephaly (severely smaller heads). Zika virus is transmitted by mosquitoes, making it an arbovirus or vectorborne virus. A combination of epidemiology, in vivo modeling, and molecular studies showed that Zika virus specifically targeted the brain cells of developing fetuses, leading to neuronal cell death, underdeveloped infant brains, and smaller heads in infected babies. Being on the frontlines of scientific investigation during an outbreak allows me to directly help people suffering from diseases that are mysterious in origin and in mechanism. Helping people understand the virus affecting them and how they may treat or prevent disease through antiviral therapy, vaccination, or by inhibiting transmission is the most rewarding part of my job. As Zika was taking hold of South America, I developed a free smart phone App called ZikaTracker with international colleagues to track the spread of the virus and the disease it was causing throughout the world. The App could be downloaded for free by anyone with a computer or smart phone, allowing them to report an incident of Zika infection, the location of the infection, and if disease was associated with the infected case. The App was designed to help the public become aware if Zika was present in their community, help scientists track the disease, and aid governments for the deployment of control and preventative measure for the insect vector.

 

Locally, Nova Scotia is experiencing an increase in the number of ticks as well as tick-transmitted diseases such as Lyme disease (caused by Borrelia species of bacteria) and tickborne viruses.   Nova Scotia has become an epicenter in Canada for tickborne infections since Nova Scotia has the highest incidence of Lyme disease in all of Canada. and is recognized as an environment capable of transmitting deadly tick viruses such as Powassan virus. Tick numbers and species have increased in the province over the past decade, which is thought to possibly be due to changes in the environment and climate such as the frequencies of warmer winters. Together, the increase of tick numbers and tickborne illness in Nova Scotia has created concern. As a result of my experience with emerging vectorborne viruses, the study of insect-transmitted pathogens is one of my areas of research at Dalhousie and IWK, allowing my work to be directly connected to health problems of Nova Scotia.

 

 

Picture 3: credit WHO

Influenza, the continually re-emerging virus

Influenza is a constantly emerging and re-emerging virus. Each flu season represents the emergence of new influenza viruses, causing disease in vulnerable humans (Picture 3). Much of my work is devoted to influenza viruses and determining how the viruses change each year, how previous infection in humans affects this year’s disease, and how a person’s first influenza infection affects all other flu infections and vaccination during their life-time. The knowledge gained from my research and my work in collaboration my colleagues at Dalhousie University, IWK Health Center, and the Canadian Centre for Vaccinology (CCfV), will lead to the building of better influenza vaccines, including a universal influenza vaccine. Since there are several types, subtypes, lineages, and strains of influenza viruses and the strains are continually changing by genetic shift and drift, a Universal Vaccine for influenza would protect people from all circulating flu viruses and eliminate the need for repetitive seasonal vaccination.

 

Discoveries and Contributions to Science

Why do some people need to be hospitalized from an influenza virus infection while others may only have mild sniffles and cough? How does age impact influenza disease? These are some of the questions that I have investigated in my research during my career.

 

As mentioned above, Influenza is a well-known reoccurring virus that can infect up to 30% of children and 15% of adults every flu season. By tracking the ages of people hospitalized from flu, it is well-known that infants and the elderly have a greater susceptibility to developing severe influenza disease, but why this occurs and how we can prevent severe disease are not entirely known.  As I was investigating the immune responses of breastfeeding infants during influenza infection in an model of infant infection, I found that infected infants are able to transmit the influenza virus to their mothers’ mammary glands during feeding.  After transmission, I found the virus infected the cells of the mothers’ mammary gland and live virus was then excreted in expressed milk.  This is the FIRST time that influenza transmission from infant to mother’s mammary gland has been shown.  My finding is a step to understanding why infants may be more susceptible to severe disease and may represent a mechanism we can use to protect infants during flu season. Furthermore, since pregnant and breastfeeding women are also high-risk groups for influenza, my research gives insight into this population as well.  My discovery was reported in This Week In Virology (TWIV) and by the Naked Scientists. Knowing that influenza virus may be able to be transmitted to a mother’s mammary gland, we are able to ask questions about why this may occur and if other respiratory viruses such as Respiratory Syncytial Virus (RSV) are also able to infect the breast.

 

Picture 4: credit CDC

Chikunguynya Virus (CHIKV) is another arbovirus transmitted by mosquitoes. It causes a human disease clinically characterized by sudden appearance of high fever, rash, headache, nausea, and severe joint pain (the defining symptom). The severe joint pain can last for months or years following infection, which highlights the importance of studying and understanding this virus’s transmission and disease. Chikungunya virus was first identified in East Africa (Tanzanian and Mozambique) and the word Chikungunya means “that which bends up”, describing the bent posture of CHIKV patients while in severe pain. Previously, CHIKV had only been found in tropical and subtropical areas of the world such as in Africa, Indian Ocean region, and Southeast Asia. The virus was only known at this time to be transmitted by the tropical mosquito Aedes aegyptii, which also transmits viruses such as yellow fever virus and dengue. But during an outbreak in the French La Reunion Island in the Indian Ocean, the virus acquired a mutation in its genome allowing it to also infect and be transmitted to humans by an additional mosquito, the Asian Tiger Mosquito, Aedes albopictus (Picture 4). This mosquito has a great habitat range and lives in tropical, subtropical, and temperate regions of the world. Since the mosquito lives in temperate regions, it is able to transmit CHIKV to people living in Europe, North America, South America, and the Caribbean.  In 2007, the first outbreak in a temperate region occurred in the Emilia Romagna region of Italy, which includes the city of Bologna. Over 200 cases of CHIKV infection were identified between July and September 2007 in the region. Since this virus and its disease had never before been seen in this temperate region of the world, it caused a strain on hospitals and mosquito control teams in the region as authorities worked to identify the infectious agent and contain the outbreak. My Italian colleagues at the University of Bologna and I investigated the reaction of the immune system during CHIKV infection in these patients.  From my research, I wanted to understand why the severe joint pain lasted for months and years in some patients. From my analysis of symptom severity, I found an association of proteins of the immune system specifically, CXCL9/MIG, CXCL10/IP-10 and antibody (IgG) levels.  These immune proteins (cytokines) and antibodies were seen in patients that had long-lasting severe joint pain.  By identifying the factors that may be contributing to joint pain during infection and after virus clearance, I can develop therapies to treat the painful disease.

 

 

Conclusions

 

Understanding emerging and re-emerging viruses and pathogens is important as the world changes with population growth and environmental shifts.  As humans move into previously untouched places on the globe, the frequency of virus spillover will increase.  My developed research program — which has already faced the challenges of ZIKV, CHIKV, and re-emerging influenza — will be ready to hunt the next emerging virus.

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