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Home , Bourbon virus, Dengue fever, Henipavirus, Kyasanur Forest disease, Marburg virus disease, Reston virus

A Review of Emerging and Re- Emerging Zoonotic of the

Ryan F. Relich, PhD, D(ABMM), MLS(ASCP)SM Assistant Professor, Clinical Pathology and Medicine Indiana University School of Medicine

Section Director, Clinical Microbiology and (Eskenazi Health) Section Director, Clinical Laboratory (IU Health) Medical Director, Special Unit Laboratory (IU Health) Associate Medical Director, Division of Clinical Microbiology (IU Health) Associate Medical Director, Division of Molecular Pathology (IU Health)

Indianapolis, IN USA Disclosures and disclaimers

• Research funding/support • Abbott, BD Diagnostics, Beckman Coulter, Cepheid, Luminex Corporation, Roche, Sekisui, STAT-Diagnostica

• Travel support by First Coast ID/CM Symposium

• PASCV sponsorship Objectives

• At the end of this presentation, audience members will be able to: • Describe the basic biology, ecology, and epidemiology of the viruses discussed;

• Identify factors associated with the emergence or re- emergence of zoonotic viruses; and,

• List clinical features of diseases caused by several zoonotic viruses, as well as their detection, treatment, and prevention. Outline

• What are emerging zoonotic viruses and where do they come from?

• Overview / introduction to selected viruses

• Role of applied and basic research in detecting and controlling these agents

• Summary What are emerging pathogens?

• “Infectious diseases whose has increased in the past 20 years and could increase in the future.” • Caused by • Newly recognized pathogens

• Old foes recurring in known areas and/or new endemic areas Where do they come from?

• The majority spill over from animals • Zoonotic

6 Where do they come from?

• Many are transmitted directly from animal reservoirs to humans or to humans through one or more other animals (e.g., pigs, dogs, camels, , etc.)

• Others are maintained by -human-arthropod

7 Why do they spill over?

• Anthropogenic drivers • Encroachment into natural

• Introduction of viruses (and other microorganisms) into new geographic locations

• Agricultural practices

• Anthropogenic

8 Why do they spill over?

• Non-anthropogenic drivers • Movement of infected reservoirs and vectors into new areas • People can have a hand in this, too!

• Adaptation of viruses to new vectors and other hosts

9 Arthropod-borne viruses

• • These viruses persist in nature by • Cycling between competent arthropod vectors and other animals (e.g., NHPs, sloths, rodents, etc.)

• Transovarial transmission (from dams to offspring)

• After introduction into human populations, some establish -human-vector cycles

10 Arthropod-borne viruses

• -borne viruses • Dengue • , ; family,

• Non-segmented, (+)ssRNA

• Enveloped particles

• 5 • Dengue 1 – 5 ViralZone

11 Arthropod-borne viruses

• Mosquito-borne viruses • • Causes dengue or “breakbone fever” • Febrile illness that can sometimes lead to severe disease and

• Dengue syndrome and hemorrhagic fever

• with one does NOT protect you against infection with others

12 Arthropod-borne viruses

• Mosquito-borne viruses • Dengue virus • Perhaps the most widely distributed on the planet; several thousand per year

CDC Arthropod-borne viruses

• Mosquito-borne viruses • Dengue virus • Vector: spp. (e.g., A. aegypti [L] and A. albopictus [R])

CDC CDC Arthropod-borne viruses

• Mosquito-borne viruses • virus • Genus, ; family, Togaviridae

• Non-segmented, (+)ssRNA

• Enveloped particles

ViralZone Arthropod-borne viruses

• Mosquito-borne viruses • Chikungunya virus • Found in both Eastern Hemisphere and Western Hemisphere • Arrived to Western Hemisphere in 2013

• Disease process • ~80% of those infected become symptomatic

• Fever, joint pain, ,

• Post-infectious can last for MONTHS Arthropod-borne viruses

• Mosquito-borne viruses • Chikungunya virus • Same as for dengue virus

CDC Arthropod-borne viruses

• -borne viruses • • Genus, ; family,

• Segmented, (-)ssRNA

• Enveloped particles

ViralZone Arthropod-borne viruses

• Tick-borne viruses • Bourbon virus • To date, only a handful of reported human disease cases

• Disease process • Unknown

• Fever, , , polymyalgia, , , , ARDS, death

• , , elevated enzymes Arthropod-borne viruses

• Tick-borne viruses • Bourbon virus • Vector: likely americanum (lone star tick)

http://heartspring.net/deer_tick_identification.html http://www.cdc.gov/ticks/maps/lone_star_tick.html Arthropod-borne viruses

• Tick-borne viruses • Heartland virus • Genus, Banyangvirus; family,

• Segmented, (-)ssRNA

• Enveloped particles

ViralZone Arthropod-borne viruses

• Tick-borne viruses • Heartland virus • To date, only a handful of reported human disease cases

• Disease process • Fever, , decreased appetite, , nausea, diarrhea, myalgia, and arthralgia

• Leukopenia, thrombocytopenia, mildly elevated liver enzymes

• A few deaths associated with infection Arthropod-borne viruses

• Tick-borne viruses • Heartland virus • Vector: (lone star tick)

CDC -borne viruses

• comprise the second-largest order of mammals • Over 1,200 species (account for about 20% of known species)

• Massiveness of bat diversity means that there’s also a great deal of virus diversity • Some have proven to be dangerous human pathogens

• Many “” under the radar, as they are nonpathogenic to humans

• Many pathogens have yet to make contact contact with people and other susceptible hosts

24 Bat-borne viruses

• Bat-borne viruses can either directly or indirectly spill over to humans • Direct: virus and other encephalitogenic lyssaviruses; filoviruses, , etc.

• Indirect: , filoviruses, henipaviruses, various coronaviruses, etc.

25 Bat-borne viruses

• Coronaviruses • Genus, Betacoronavirus; family, • Enveloped particles

• Monopartite (+)ssRNA

• Particles have distinct morphology

ViralZone Bat-borne viruses

• Coronaviruses • Etymology • Corona = Latin noun, “crown”

Wikipedia Beth Fischer, NIAID RML Bat-borne viruses

• Coronaviruses • Middle East respiratory syndrome coronavirus (MERS-CoV or “Merbecovirus”) • First recognized in 2012 • Isolated from a Saudi Arabian patient’s sputum  patient had pneumonia and renal failure

• Clusters of cases in other parts of the Middle East (e.g., Jordan, Qatar, UAE, Yemen, etc.) --> sporadic cases outside of Middle East

• 2015: large outbreak in South Korea Bat-borne viruses

• Coronaviruses • MERS-CoV

Virology Down Under 2019 Novel Coronavirus

• 2019-nCoV • A ”new” betacoronavirus distantly related to SARS-like CoVs emerged in late 2019 (Wuhan, China)

May and Relich. 2020. Unpublished. 2019 Novel Coronavirus

• 2019-nCoV • A ”new” betacoronavirus distantly related to SARS-like CoVs emerged in late 2019 (Wuhan, China)

May and Relich. 2020. Unpublished. 2019 Novel Coronavirus

• 2019-nCoV • Currently, >12,000 cases in China and beyond • As of Jan 31, 2020 - 26 countries reporting cases 2019 Novel Coronavirus

CDC (from Jan 31, 2020) 2019 Novel Coronavirus

• 2019-nCoV • Currently, >12,000 cases in China and beyond • As of Jan 31, 2020 - 26 countries reporting cases • 7 confirmed cases in the U.S. 2019 Novel Coronavirus

CDC (from Jan 31, 2020) 2019 Novel Coronavirus

• 2019-nCoV • Currently, ~12,000 cases in China and beyond • As of Jan 31, 2020 - 26 countries reporting cases • 6 confirmed cases in the U.S.

• Approximately >250 deaths (China)

• Person-to-person transmission is possible Bat-borne viruses

• Filoviruses • Currently, 6 recognized genera • Non-segmented (-)ssRNA

• Enveloped particles • Filamentous morphology

ViralZone

37 Bat-borne viruses

• Filoviruses • Cuevavirus (1 species) • Dianlovirus (1 virus) • (6 species) • (1 species) • Striavirus (1 virus) • Thamnovirus (1 virus)

38 Bat-borne viruses

• Filoviruses • Naturally found in the Eastern Hemisphere • Europe, Africa, China, , elsewhere? • , virus, and virus have all been exported to non-native countries

• Human-pathogenic filoviruses often cause severe disease • Ebola virus disease (Ebola hemorrhagic fever) • disease Bat-borne viruses

• Filoviruses • Some (potential) reservoirs • Schreiber’s long-fingered bat (Miniopterus schreiberi) – LIoviu cuevavirus

• (Rousettus egyptiacus) – Marburg virus

• African and Asian fruit bats – a variety of and Měnglà viruses Bat-borne viruses

• Filoviruses Bat-borne viruses

• Henipaviruses • Genus, ; family, • Non-segmented (-)ssRNA

• Enveloped particles

• So far, there are 5 named henipaviruses

ViralZone

42 Bat-borne viruses

• Henipaviruses • Cedar henipavirus • Ghanian bat henipavirus • Hendra henipavirus • Mojiang henipavirus • Nipah henipavirus

43 Bat-borne viruses

• Henipaviruses • Hendra and Nipah viruses are found in Australia and Asia, respectively, and are reservoired by large fruit bats (flying foxes) • spp.

Pteropus lyeli (dukelanguage.com) Bat-borne viruses

• Henipaviruses

CDC Bat-borne viruses

• Henipaviruses • • Causes respiratory and CNS disease in pigs and other animals

• Humans have become infected by contact with infectious bat excrement (through consumption), through contact with infected pigs, and by person-to-person transmission

• Causes severe -like and/or severe CNS disease in humans • High case fatality rates (~40 – 100%) in most outbreaks Bat-borne viruses

• Henipaviruses • Nipah virus

Malaysia de Wit et al. 2015. J Pathol 235:196-205 Rodent-borne viruses

• Rodents comprise the largest order of mammals • Over 2,200 species (account for about 40% of described mammal species)

• Massiveness of rodent diversity means that there’s also a great deal of virus diversity • Some have proven to be dangerous human pathogens

• Many “scurry” under the radar, as they are nonpathogenic to humans

• Many pathogens have yet to make contact with people and other susceptible hosts

48 Rodent-borne viruses

• Rodents comprise the largest order of mammals • Transmission is similar to that of bat-borne viruses • Direct – physical contact infectious rodent excreta, inhalation of infectious

• Indirect - contamination of foodstuffs

49 Rodent-borne viruses

• • “Old World” viruses - Lassa virus, Lujo virus, lymphocytic choriomeningitis virus

• “New World” viruses - South American hemorrhagic fever viruses, Whitewater-Arroyo virus, and others

• These viruses can cause severe, and sometimes fatal human diseases • Hemorrhagic fever • CNS disease

50 Rodent-borne viruses

• Arenaviruses

Arenavirus Rodent Reservoir Disease

Chapare virus Unknown HF Guanarito virus Common cane mouse (Zygodontomys brevicauda) HF Junin virus House mouse (Mus musculus), Drylands vesper mouse HF (Calomys musculinus), Azara’s grass mouse (Akodon azarae) Lassa virus Natal multimammate mouse (Mastomys natalensis) HF Lujo virus Unknown HF Lymphocytic choriomeningitis virus House mouse (Mus musculus) CNS disease Machupo virus Large vesper mouse (Calomys callosus) HF Sabia virus Unknown HF Whitewater-Arroyo virus Woodrats (Neotoma spp.) HF Rodent-borne viruses

• Arenaviruses • Genus, Mammarenavirus; family, Arenaviridae • Enveloped particles

• Segmented (-)ssRNA

• Contain ribosomes • Electron-dense “spots”

ViralZone

52 Rodent-borne viruses

• Lassa virus • Found primarily in

Stanford Rodent-borne viruses

• Lassa virus • Found primarily in West Africa

• Reservoired by natal multimammate mouse (M. natalensis)

Kokofeed.com Rodent-borne viruses

• Lassa virus • Up to 500,000 cases per year have been reported • Most cases are not severe

• ~20% of patients develop more serious : hemorrhagic fever, ARDS, facial swelling, , etc.

• Supportive care and ; barrier care precautions are key to treatment and containment Rodent-borne viruses

• Hantaviruses • Genus, ; family, Hantaviridae • Segmented (-)ssRNA

• Enveloped particles

ViralZone Rodent-borne viruses

• Hantaviruses • Reservoir • Rodents and some bats are the reservoirs

• Reservoirs are subclinically infected; despite this, can be very high and viruses are detected in various tissues (e.g., kidneys, lungs, GI tissues, etc.)

• Transmission most commonly occurs secondary to inhalation of virus-laded rodent excreta Rodent Hantavirus(es) Disease

California vole (Microtus californicus) Convict Creek; Isla Vista HPS Montane vole (Microtus montanus) El Moro Canyon; Prospect Hill Unknown Prairie vole (Microtus ochrogaster) Bloodland Lake Unknown Meadow mole (Microtus pennsylvanicus) Prospect Hill Unknown Desert woodrat (Neotoma lepida) Sin Nombre HPS

Mexican woodrat (Neotoma mexicana) El Moro Canyon Unknown Rice rat (Oryzomys palustris) Bayou HPS Brush mouse (Peromyscus boylii) Limestone Canyon; Prospect Hill; Sin Nombre Unknown and HPS California mouse (Peromyscus californicus) Isla Vista; Sin Nombre HPS White-footed mouse (Peromyscus leucopus) Blue River; Monongahela; New York; Sin Nombre HPS Deer mouse (Peromyscus maniculatus) Convict Creek; El Moro Canyon; Monongahela; HPS Prospect Hill; Sin Nombre Pinyon mouse (Peromyscus truei) Prospect Hill; Sin Nombre HPS Western harvest mouse (Reithrodontomys megalotis) El Moro Canyon; Huitzilac; Sin Nombre HPS Hispid cotton rat (Sigmodon hispidus) Bayou; Black Creek Canal; Muleshoe HPS House mouse (Mus musculus) Dobrava-; Leakey; Prospect Hill; Seoul; Sin HFRS; HPS Nombre Brown rat (Rattus norvegicus) Andes; Seoul; Tchoupitoulas HFRS; HPS Cliff chipmunk (Tamias dorsalis) Prospect Hill; Sin Nombre HPS Least chipmunk (Tamias minimus) Convict Creek Unknown Long-eared chipmunk (Tamias quadrimaculatus) Prospect Hill Unknown Rodent-borne viruses

• Hantaviruses • Diseases • Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS)

• High (up to 40% in some outbreaks)

• No specific treatment or available Diagnosis, treatment, and prevention strategies

• Diagnosis • Early recognition of these pathogens is key to rendering a clinical diagnosis • Education of healthcare providers about • Disease epidemiology and risk factors • Signs and symptoms • Selection and interpretation of diagnostic tests, if they exist • Infection control and containment strategies • Treatment protocols, if they exist • Prevention / prophylaxis protocols, if they exist

60 Diagnosis, treatment, and prevention strategies

• Diagnosis • The role of clinical and public health • Testing for pathogens • Direct detection (PCR, NGS, culture, TEM)

• Indirect detection (test for -specific IgM and IgG) • Following detection of , perform PRNT for confirmation

61 Diagnosis, treatment, and prevention strategies

• Diagnosis • The role of clinical and public health laboratories • For many of these pathogens, tests are not available to clinical laboratories

• For some pathogens, screening and confirmatory testing requires enhanced and practices

62 Diagnosis, treatment, and prevention strategies

Andrea Marzi (L) and Dana Scott (top) NIAID RML, Hamilton, MT

63 Diagnosis, treatment, and prevention strategies

• Treatment • For many of these viruses, specific treatments are not yet available • Treatment consists of supportive care

• Antivirals such as , ribavirin, , Zmapp, and others are promising • Depends upon the virus

64 Diagnosis, treatment, and prevention strategies

• Treatment • In some instances, treatment requires the use of specialized biocontainment rooms and appropriate PPE • Complicates the care of diseased patients

• Negatively affects the emotional well-being of patients

• Comes with a high price tag

• Not available at all healthcare facilities

65 Diagnosis, treatment, and prevention strategies

• Prevention • Avoidance of vectors or reservoir hosts • Use of and repellants

• Pest management • Discourage vector or reservoir colonization of residential areas

• Seal homes and other dwellings to prevent infestations

• Safely trap and dispose of animals likely to be infected with pathogens

66 Diagnosis, treatment, and prevention strategies

• Prevention • • to prevent most of the viruses described herein are not available

• There are a few, though • rVSV-ZEBOV • Dengvaxia (given after initial DENV exposure) • vaccine • fever vaccine • Argentine hemorrhagic fever vaccine • vaccine (horses only)

67 Diagnosis, treatment, and prevention strategies

• Prevention • Education • Of populations in disease-endemic regions • Transmission • Prevention of spread (e.g., social distancing, abstinence) • Signs and symptoms of disease • Safe care and practices

• Of healthcare providers • Early recognition of signs and symptoms • Diagnostic test utilization • Containment, treatment, and prevention protocols

68 Emerging zoonotic virus research

• Basic, applied, and translational research is of paramount importance for combating infectious diseases • Understanding the ecology, epidemiology, and pathogenesis of these agents is key to mitigating threats • Better diagnostics need to be developed • Better treatment strategies need to be developed • Surveillance of vectors and other animals is important in determining risks posed to human and other animal populations • Additional vaccines for both humans and animals are needed • The list goes on and on…

• This all requires FUNDING! • Perhaps we will someday reprioritize and put the health of animals, plants, and people at the top of the list

69 Summary

• A whole slew of arboviruses, bat-borne, and rodent-borne viruses pose (significant) threats to global public health • We didn’t even talk about viruses carried by other animals

• Better surveillance, diagnostic, treatment, and prevention measures are needed

• Education of susceptible people and healthcare providers is key to early disease recognition, containment, treatment, and prevention

• Research into these pathogens is absolutely required to mitigate the threats that they pose

70 Acknowledgements

• Relich Laboratory • Indiana University • Guang-Sheng (Bob) Lei • Daniel Becker • Keith Clay • National Institutes of Health • Laboratory of Virus Ecology • Mayo Clinic • Vincent Munster • Elli Theel • Neeltje van Doremalen • Hideki Ebihara • Jeremiah Matson • Centers for Disease Control • Disease Modeling and Transmission • Brandy Russell • Heinz Feldmann • Elaine Haddock • Kristy Burkhalter • Andrea Marzi • University of New England • Neuroimmunology Unit • Meghan May • Karin Peterson