CORONAVIRUS - College of William & Mary

CORONAVIRUS

NANOPARTICLE KILLING MACHINE

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CORONAVIRUS OUTLINE

• Strains and origin

• Transmission

• Replication

• Pathogenesis

• Cytokine Storm

• Antigen and Antibody Testing

• Treatment

• Vaccines

• Cytotoxic T-cells

• Herd Immunity

• Mouse Model

• DEFINITIONS

• SARS - Severe acute respiratory syndrome – Viral respiratory illness

• CORONAVIRUS - Any of a family of single stranded RNA viruses that have a lipid envelope studded with club shaped projections. Infect birds and mammals.

• SARS-COV-1 - Virus arising in China in 2002

• SARS-COV-2 - Virus arising in China in 2019

• COVID-19 - SARS caused by Cov-2

CORONAVIRUS FAMILIES

CORONAVIRUS FAMILIES

SARS CoV-2 CAME FROMBAT RELATED STRAINS

• Correspondence

• Published: 17 March 2020

• The proximal origin of SARS-CoV-2

• Kristian G. Andersen, Andrew Rambaut, W. Ian Lipkin, Edward C. Holmes & Robert F. Garry

• Nature Medicine volume 26, pages450–452(2020)

• To the Editor — Since the first reports of novel pneumonia (COVID-19) in Wuhan, Hubei province, China1,2, there has been considerable discussion on the origin of the causative virus, SARS-CoV-23 (also referred to as HCoV-19)4. Infections with SARS-CoV-2 are now widespread, and as of 11 March 2020, 121,564 cases have been confirmed in more than 110 countries, with 4,373 deaths5.

• SARS-CoV-2 is the seventh coronavirus known to infect humans; SARS-CoV, MERS-CoV and SARS-CoV-2 can cause severe disease, whereas HKU1, NL63, OC43 and 229E are associated with mild symptoms6.

• Here we review what can be deduced about the origin of SARS-CoV-2 from comparative analysis of genomic data. We offer a perspective on the notable features of the SARS-CoV-2 genome and discuss scenarios by which they could have arisen.

• Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus

Los Alamos National Lab.

Daily Mail, May 5

MUTANT CLADE D614G

Spike protein

Clade - A group of organism believed to have evolved from a common ancestor.

G614

NATURAL SELECTION

MUTATIONS THAT PERSISTMAKE VIRUS MORE CONTAGOUSAND LESS VIRULENT

ITALY

CHINA

NEW YORK

Mutant strain of coronavirus has “dominated” the US and Europe –And vaccines in development may NOT work against it.

MAY 1 2020

TRANSMISSION

TO BREAK EPIDEMIC MUST HAVE R0 BELOW 1

TRANSMISSION RATE

VIRAL REPLICATION

VIRUS TAKES OVERCELL METABOLICPATHWAYSTO MAKE MOREVIRUS

AFRICAN GREEN MONKEY KIDNEY CELLS Vero E6; MA 104

CYTOPATHIC EFFECT

CaCo-2 Human colorectal cancer cells

ACE2 EXPRESSION

DOUBLING TIME 24 HOURS

The Nobel Prize in Physiology or Medicine 1954 was awarded jointly to John Franklin Enders, Thomas HuckleWeller and Frederick Chapman Robbins "for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue.".

JOHN ENDERS

Not to Jonas Salk or Albert Sabin

LISINOPRIL - ACE INHIBITOR

SARS CoV2 RECEPTOR ACE – ANGIOTENSIN CONVERTING ENZYME

Coronavirus

PATHOGENESIS KILLS ACE+ CELLS

CoV 2 TWO WEEKS

SARS CoV-2 INFECTS BRNCHIAL LINING CELLS AND PNEUMOCYTES

ACUTE SARS TOXICITY OF BRONCHIAL LINING CELLS CELLS

CoV 2 TWO + WEEKS

TWO TYPES OF ALVEOLAR EPITHELIAL CELLS

LUNG FUNCTION WITH AGING - FORCED EXIRATORY VOLUME

CONUNDRUMNo evidence smokerswith Covid -19 doworse than non-smokers.

NYU LANGONE MEDSIRUS XMDOCTOR’S CHANEL

ACE IN INTESTINAL CELLS SARS-CoV 2 BINDING TO INTESTINE

1.cytokine storm syndrome2. direct cellular injury due to the virus.

Naicker S, et al. The novel coronavirus 2019 epidemic and kidneys, Kidney Int. 97:824-828, 2020

EXTRAPULMONARY MANIFESTATIONSINTESTINE/KIDNEY

ACE2 IN RENAL TUBULES

Control Labelled

ITALY - CHICKEN POX-LIKE (T-CELLCYTOXICITY) HIVES-LIKE (ATOPIC) TAILAND DENGUE-LIKE (T-CELL)

TAILAND PETECHE (CYTOTOIC/PLATELETS) US PERNIOSIS/CHILBLANES (?IMMUNE CPLX) LIVIDO RETICULARIS (?ATOPIC)

DERMATOLOGY SOLUTIONS SKIN LESIONS DERMATOLOGIST’S DELIGHT OR DELEMA

IMMUNE MECHANISM PROTECTIVE DESTRUCTIVE/ DISEASE COVID -19 SKIN LESION

NEUTRALIZATION BLOCK VIRUS BINDING DIABETES, MYASTHENIA GRAVIS

CYTOLYTIC LYSE BACTERIA HEMOLYTIC ANEMIA, PLATELETS PETECHIE

IMMUNE COMPLEX INFLAMMATION VASCULITIS, GLOMERULONEPHRITIS PERNIOSIS/CHILBLANES

ATOPIC/ANAPHYLACTIC VASODILATION ASTHMA, ANAPHYLAXIS, HAY FEVER HIVES, LIVIDO RETICULARIS

DOUBLE EDGED SWORD OF ANTIBODY MEDIATED IMMUNE REACTIONS

Paratope

MANY THINGS CAN HAPPEN WHEN ANTIBIDY-ANTIGEN REACTION OCCURS IN THE BODY (IN VIVO)

KAWASAKI DISEASE POLYMORPHONUCLEAR MEDIATED VASCULAR NECROSIS IMMUNE COMPLEX MECHANISM

Pediatric Multi-System Inflammatory Syndrome Potentially Associated with COVID-19,' can attack multiple organs, impair heart function and weaken heart arteries.

NEW SYNDROME MAY 2020

Pediatric Multi-System Inflammatory Syndrome Associated with COVID-19.Can attack multiple organs, impair heart function and weaken heart arteries.102 cases in New York and three children, ages 5, 7, and 18, have died

POSSIBLE COMBINATION OF:

VIRAL INJURY

CYTOKINE STORM

IMMUNE COMPLEX

• Purple rashes, swollen legs, clogged catheters and sudden death — blood clots, large and small, are a frequent complication of COVID-19

• Endothelial cell infection and/or injury (CYTOTOXIC)

• Inflammation (IMMUNE COMPLEX, CYTOKINE STORM)

BLOOD CLOTTING

LOSS OF SMELL (ANOSMIA) AND TASTE (DYSGUESIA)

I only have mild coronavirus symptoms but whatever I’ve got has absolutely obliterated my sense of taste and smell. To test I have had:- a teaspoon full of curry powder - a glass of very concentrated grapefruit squash - a clove of garlic none of which taste of anything.

Jon Stone Twitter

DIRECT INFECTION OF CELLSINFLAMMATIONTARGET DECTECTOR CELLS ?

Figure 1a: A, Image from noncontrast head CT demonstrates

symmetric hypoattenuation within the bilateral medial thalami

(arrows). B, Axial CT venogram demonstrates patency of the

cerebral venous vasculature, including the internal cerebral veins

(arrows). C, Coronal reformat of aCT angiogram demonstrates

normal appearance of the basilar artery and proximal posterior

cerebral arteries.

Acute necrotizing encephalopathy (ANE) is a rare

complication of influenza and other viral infections and has

been related to intracranial cytokine storms, which result in

blood-brain-barrier breakdown, but without direct viral

invasion or parainfectious demyelination (3). Accumulating

evidence suggests that a subgroup of patients with severe

COVID-19 might have a cytokine storm syndrome (4).

Reviews and CommentaryFree Access

Images in Radiology

COVID-19–associated Acute Hemorrhagic Necrotizing Encephalopathy: CT

and MRI FeaturesNeo Poyiadji, Gassan Shahin, Daniel Noujaim, Michael Stone, Suresh Patel, Brent Griffith

Author Affiliations

•From the Department of Radiology, Henry Ford Health System, 2799 West Grand Blvd Detroit MI 48202.

•Address correspondence to B.G. (email: brentg@rad.hfh.edu).

BRAIN

HEART INCREASED HYPOXIA FROM LUNG DAMAGE

EXACERBATED BY HYDROXYCHLOROQUINE

CYTOKINE STORM

WILLIAM COLEY1892

1890’s WILLIAM COLEY

1893 - Coley produces Coley's toxin - extract of cultures of S. Pyogenes and B. prodigiosus (endotoxin producer)

1893 - Coley treats John Ficken, 13 year old boy with inoperable metastatic tumors by direct injection of toxin into tumors, severe fever and chills, tumors go away

1913 - Coley has treated over 500 patients, claims many remissions. However, others not successful. considerable controversy.

1926 - Some anecdotal cases of remission still reported.

Dr. Coley's experience with occasional incredible cures, lack of consistency and failure of others to duplicate results haunts cancer immunotherapy to this day.

In 1920's Coley's toxins not accepted for cancer therapy as radiation therapy becomes in vogue.

STEPHEN S. HALL

A COMMOTION IN THE BLOOD

HENRY HOLT & CO.NEW YORK

1997

CYTOKINE STORM MEDIATORSPRODUCED BY T-CELLS MACROPHAGES

IL-2 T-CELL PROLIFERATION IL-1 T-CELL ACTIVATIONIL-3 STIMULATES HEMATOPOIESIS IL-12 ACTIVATES NK CELLSIL-4 STIMULATES B-CELLS (IgE, IgA) Th1 DIFFERENTIATIONIL-5 EOSINOPHIL DIFFERENTIATION IL-18 STIMULATES INF-γIL 6 MUTIPLE EFFECTS Th1 DIFFRENTIATIONIL-8 ATTRACTS/ACTIVATES PMNs TGF-β INHIBITS CELL GROWTHIL-9 ACTIVATES MAST CELLS INF-α INCREASES MHC I EXPRESSIONIL-10 SUPRESSES MACROPHAGES TNF-α ACTIVATES ENDOTHLIAL CELLSIL-13 Th2 DIFFERENTIATION (CACHEXIN) TUMOR NECROSISIL-15 ACTIVATES NK CELLSIL-16 ATTRACTS CD4+T-CELLSIL-17 MUTIPLEINF-γ ACTIVATES MACROPHAGESTNF-β KILLS CELLS

IL-6 PRODUCED BY MANY CELL TYPES UNDER STRESS

ACTIVATES MANY CELL TYPES

TOCILIZUMAB (ACTEMRA)HUMAN MONOCLONAL ANTIBODY TO IL-6 RECEPTOR

BLOCKS IL-6 REACTION WITH RECEPTOR

CLINICAL TRIALS PLANNED ESTIMATED START DATE MAY 30, 2020

ANTIGENNASAL SECRETIONSSALIVA

PCR AND IMMUNE LABELING

ANTIBODY SERUM

IMMUNE LABELING

CORONAVIRUS TESTING

DNAP – DNA POLYMERASE

NASAL/SALIVART-PCR REAL TIME POLYMERASE CHAIN REACTION

EACH TIME AN DNA COPY IS PRODUCEDA FLUORESCENT LABEL IS RELEASEDAND THIS IS DETECTED BY ABSORPTIONAND EMISSION SHIFT

TEST FOR ANTIGEN

TEST FOR ANTIBODY

IMMUNOLABELLING TESTS

FLUORECENCENT LABELLED M0USE MONOCLONAL ANTIBODY BINDING TO SARS CoV-2 SPIKE PROTEIN IN INFECTED BHK TISSUE CULTURE CELLS NUCLEI COUNTERSTAINED WITH DAPI (BLUE)

BHKBABY HAMSTER KIDNEY

PROBLEM FALSE NEGATIVES

CORIS SARS -CoV STRIP TEST FOR ANTIGEN

CONTROL LINE VIRAL ANTIGEN POSITIVE

TEST LINE CAPTURE ANTI-VIRAL ANTIGEN

San Diego–based Quidel describes the Sofia 2 SARS Antigen FIA as a rapid point-of-care test to be used with the Sofia 2 fluorescent immunoassay analyzer.

Kit cost ?$500 25 tests

$910.95

$618.00

IMMUNOLABELLING FOR NUCLEOCAPSID ANTIGEN

FDA APPROVED

May 8, 2020

Today, the U.S. Food and Drug Administration authorized the first diagnostic test with the option of using home-collected saliva samples for COVID-19 testing. Specifically, the FDA issued an emergency use authorization (EUA) to Rutgers Clinical Genomics Laboratory for their COVID-19 laboratory developed test (LDT), which had been previously added to the high complexity molecular-based LDT “umbrella” EUA, to permit testing of samples self-collected by patients at home using the Spectrum Solutions LLC SDNA-1000 Saliva Collection Device. This announcement builds on last month’s EUA for the first diagnostic test with a home-collection option, which uses a sample collected from the patient’s nose with a nasal swab and saline.

SALIVA TEST

ENTERTAINMENT INDIA

Madonna Tests Positive For Coronavirus Antibodies

ANTIBODIES

NEUTRALIZING ANTIBODY TEST

TESTS FOR ANTIBODY

BINDS ANTIGEN

BIOLOGIC PROPERTIES

Ig CLASS ANTIGENS ANTI-Ig

ANTIBODY CLASSES

COVID 19 ANTIBODY TEST KIT $250

POSITIVE CONTROL

DILEMA

WHAT TO USEAS COVID-19 ANTIGEN?

SPECIFIC ANTIBODIESDETECTEDIN SARSPATIENTS

S-PROTEINNUCLEOCAPSID

RocheElecsys Anti-SARS-Cov 2

Electrochemiluninence

Nucleocapsid antigen

500 tests per day at $100/testFDA APPROVED

Electrochemiluminescence (electrogenerated chemiluminescence, ECL) is an energy- relaxation process by optical emission of an excited molecule produced by an applied potential at an electrode surface [1–7].

Cohort Sample number (N) Reactive Specificity % (95 % CI*)

Diagnostic routine 3420 7 99.80 % (99.58 – 99.92 %)

Blood donors 1772 3 99.83 % (99.51 – 99.97 %)

Common cold panel 40 0 100 % (91.19 – 100 %)

Coronavirus panel 40 0 100 % (91.19 – 100 %)

Overall 5272 10 99.81 % (99.65 – 99.91 %)

Days post PCR confirmation Sample number (N) Sensitivity (95 % CI)

0 – 6 days 116 65.5 % (56.1 – 74.1 %)

7 – 13 days 59 88.1 % (77.1 – 95.1 %)

≥14 days 29 100 % (88.1 – 100 %)

WHY HAVE WE BEEN

SO FAR BEHIND IN TESTING?

INFECTION OF PETS?

• Washington, D.C. April 22, 2020 – The U.S. Centers for Disease Control and Prevention (CDC) and the United States Department of Agriculture’s (USDA) National Veterinary Services Laboratories (NVSL) today announced the first confirmed cases of SARS-CoV-2 (the virus that causes COVID-19) infection in two pet cats. These are the first pets in the United States

• Public health officials are still learning about SARS-CoV-2, but there is no evidence that pets play a role in spreading the virus in the United States. Therefore, there is no justification in taking measures against companion animals that may compromise their welfare. Further studies are needed to understand if and how different animals, including pets, could be affected.

1914 serum samples from 35 animal species were

used for detection SARS‐CoV‐2 specific antibodies

using double antigen sandwich ELISA after validating

its specificity and sensitivity.

no SARS‐CoV‐2 specific antibodies were detected

Serological survey of SARS‐CoV‐2 for experimental, domestic, companion and wild animals excludes

intermediate hosts of 35 different species of animals

Junhua Deng Yipeng Jin Yuxiu Liu Jie Sun Liying Hao Jingjing Bai Tian Huang Degui Lin Yaping

Jin Kegong Tian. Transboundry and Emerging Diseases. April 17, 2020

TREATMENT AND PREVENTION

109

MOUSE MODEL MACQUES

DRUG DISCOVERY FLOW CHART

Actemra, Kevzara IL-6 INHIBITORS

NIH study reduced hospitalization by 4 days (15 to 11)

Previous study in China showed no effect (Discontinued)

Side effects. Nausea, vomiting, increased liver enzymes

Emergency (Compassionate) approval by FDA

Other trials still underway.

VITAMIN D CONCENTRATIONS ABOVE 50 ng/ml WERE ASOCIATED WITH A 25% REDUCTION IN INFLUENZA-LIKE ILLNESSES

MP –METHYLPREDNISONE SOURCE OF DATA UNKNOWN

CONVALESCENT PLASMA THERAPYNOT STANDARDIZED

REQUIRES DONATIONPOSITIVE EFFECT: ONLY PRELIMINARY DATA FOR COVID -19

HUMANIZED MONOCLONAL ANTIBODYSTANDARDIZEDLAB MADE

scFv – Single chain variable fragmentAntigen binding site - paratope

DNAInfected phage display protein scFvBind antigen

VACCINES INACTIVATION / NEUTRALIZATION

TOXIN NEUTRALIZATIONBACTERIA TOXINS

TETANUS DIPHTHERIA PERTUSSIS CHOLERA ANTHRAX

RECEPTOR BLOCKADEVIRUSES

MEASLES FLU EBOLA HEPATITISHERPESPOLIOPAPILLOMA ETC.

SARS CoV-2 POTENTIAL IMMUNOGENS

S-PROTEIN VACCINES

•egg-based flu vaccine,

•cell-based flu vaccine, and

•recombinant flu vaccine.

Most common

Egg-based vaccine manufacturing is used to make

both inactivated (killed) vaccine (usually called the “flu

shot”) and live attenuated (weakened) vaccine (usually

called the “nasal spray flu vaccine

ANTIGENIC COMPONENTS OF HEMGGLUTININ CHANGE EVERY FLU SEASON, NEW VARIENTS ARE SELECTED FOR EACH YEAR,

INFLUENZA VACCINE KILLED OR WEAKENED VIRUS

HEMAGGLUTININ

MODERNAmRNA-1273Spike protein

DA approved forPhase 2 clinical trials

TEST FOR ANTIBODY TEST FOR ANTIBODY DOUBLE BLIND

VARIOUS LEVELS OF VIRAL PROTECTIVE IMMUNITY

1. ANTI-VIRUS 2. ANTI-CELL MEMBRANE 3. T-CTL

DOUBLE EDGED SWORD OF CELL MEDIATED IMMUNE REACTIONS

T-CELL MEDIATED IMMUNE MECHANISMS

T-CYTOTOXIC DELAYED HYPERSENSITIVITY

IMMUNE MECHANISM PROTECTIVE DESRUCTIVE

T-CYTOTOXIC KILL VIRUS INFECTED CELLS THYROIDITIS, CHRON’S DISEASE

DELAYED HYPERSENSITIVITY TUBERCULOSIS, SYPHILIS SARCOIDOSIS, SILICOSIS

CYTOTOXIC T CELLS

Antigen

COV 2 TWO WEEKS

WHAT IF ANTIBODY DOSEN’T WORKSARS COV2 INFECTS EPITHELIUM

CIRCULATING ANTIBODY MAY HAVE LIMITED ACCESS TO INFECTED BRONCHIAL EPITHELIAL CELLS

BRONCHUS NORMAL – NOT INFECTED

GOBLET CELLS

BASEMENTMEMBRANE

LYMPHOCYTES

ARTERY

SUZY SWAINU. MASS

KAI McKINSTRYUCF

TARA STRUTTUCF

FLU INFECTED – DAY 8

EXPERIMENTAL INFLUENZA MOUSE MODEL

Br

H&E

BRONCHIAL EPITHELIUM AND TYPE II PNEUMOCYTSINFILTRATED BY T-CELLS – DAY 8

CD3 CD3

MOUSEFLU

PASSIVETRANFEROF MEMORYT-CELLS

HUMANCOVID 19

NORMALINFECTED

NORMAL SKIN CONTACT DERMATITIS

CONTACT DERMATITIS-LIKE LESION IN THE LUNG

NICKEL DERMATITIS

MEASLESPOISON IVY

SMALLPOX

COVID 19 - POISON IVY OF THE LUNG

Sell, S McKinstry KK, Strutt TM. Mouse models reveal role of T-Cytotoxic and T-Reg cells in immune response to Influenza: Implications for vaccine design. Viruses. 2019 11,52, doi:10.3390/v11010052

HOW TO DIRECT IMMUNE RESPONSE TO CYTOTOXIC T-CELLS

SMALLPOXVACCINATION TAKE

OR NONE OF THE ABOVESEASONAL OR RANDOM OUTBREAKS

kill humans

HERD IMMUNITY

MITIGATION MIXED HEARD IMMUNITY

CHINA US BRAZILSOUTH KOREA EUROPE SWEDENNEW ZEALAND

?

CONTACT TRACING

IDENTIFICATIONTRACINGISOLATEFOLLOW UP

At its simplest, digital contact tracing might work like this: Phones log their own locations; when the owner of a phone tests positive for COVID-19, a record of their recent movements is shared with health officials; owners of any other phones that recently came close to that phone get notified of their risk of infection and are advised to self-isolate.

HOW TO HANDLE?

• ECONOMISTS OPEN

• EPIDEMIOLOGISTS CLOSE

• ETHTHESISTS DOLLARS VS LIVES

THE PANDEMIC PROBLEM

MOUSE MODEL

FAST TRACK TO STUDY

PATHOGENESISIMMUNE RESPONSETREATMENTVACCINATION

Angiotensin converting enzyme – angiotensin is a vasoconstrictive peptide

K18-hACE2 transgenic mouse for coronavirus research

In 2007, Dr. Paul McCray, et al from the University of Iowa published a study in which they introduced a vector carrying a human ACE2-coding sequence into wild-type mice and subsequently developed a successful hACE2 transgenic mouse strain. ACE2 expression, which is regulated by the human cytokeratin 18 (K18) promoter in epithelial cells, was observed in the initially infected airway epithelial cells. Studies showed that the K18-hACE2 transgenic mouse infected with a human SARS-CoV strain via intranasal inoculation would not survive.

•

• Virol. 2007 Jan;81(2):813-21. Epub 2006 Nov 1.

• Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus.

• McCray PB Jr1, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L, Netland J, Jia HP, Halabi C, Sigmund CD, MeyerholzDK, Kirby P, Look DC, Perlman S.

• The severe acute respiratory syndrome (SARS), caused by a novel coronavirus (SARS-CoV), resulted in substantial morbidity, mortality, and economic losses during the 2003 epidemic. While SARS-CoV infection has not recurred to a significant extent since 2003, it still remains a potential threat. Understanding of SARS and development of therapeutic approaches have been hampered by the absence of an animal model that mimics the human disease and is reproducible. Here we show that transgenic mice that express the SARS-CoV receptor (human angiotensin-converting enzyme 2 [hACE2]) in airway and other epithelia develop a rapidly lethal infection after intranasal inoculation with a human strain of the virus. Infection begins in airway epithelia, with subsequent alveolar involvement and extrapulmonary virus spread to the brain. Infection results in macrophage and lymphocyte infiltration in the lungs and upregulation of proinflammatory cytokines and chemokines in both the lung and the brain. This model of lethal infection with SARS-CoV should be useful for studies of pathogenesis and for the development of antiviral therapies.

Weight loss and virus replication in lung were observed in hACE2 mice

infected with SARS-CoV-2. The typical histopathology was interstitial

pneumonia with infiltration of significant lymphocytes and monocytes in

alveolar interstitium, and accumulation of macrophages in alveolar

cavities. Viral antigens were observed in the bronchial epithelial cells,

alveolar macrophages and alveolar epithelia. The phenomenon was not

found in wild type mice with SARS-CoV-2 infection. against SARS-CoV-2

The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic MiceLinlin Bao, Wei Deng, Baoying Huang, Hong Gao, Jiangning Liu, Lili Ren, Qiang Wei, Pin Yu, Yanfeng Xu, FeifeiQi, Yajin Qu, Fengdi Li, Qi Lv, Wenling Wang, Jing Xue, Shuran Gong, Mingya Liu, Guanpeng Wang, Shunyi W

ang, Zhiqi Song, Linna Zhao, Peipei Liu, Li Zhao, Fei Ye, Huijuan Wang, Weimin Zhou, Na Zhu, Wei Zhen, Haisheng Yu, Xiaojuan Zhang, Li Guo, Lan Chen, Conghui Wang, Ying Wang, Xinming Wang, Yan Xiao, QiangmingSun, Hongqi Liu, Fanli Zhu, Chunxia Ma, Lingmei Yan, Mengli Yang, Jun Han, Wenbo Xu, Wenjie Tan, Xiaozhong Peng, Qi Jin, Guizhen Wu, Chuan Qin. Prepublication. Cold Spring Harbor bioRxiv, February 2020.

UPDATE 2/25/2020: This model is now available for preorder. JAX is using state-of-the-art breeding techniques to rapidly build this colony. We will notify those who preorder when the mice are available for distribution. To learn more about this mouse model and other infectious disease models from The Jackson Laboratory please contact: micetech@jax.org - 1.800.422.6423 (US) - 1.207.288.5845 (International).

ABAILABLE FROM JACKSON LABORATORY

CORONAVIRUS OUTLINE• Strains and origin

• Transmission

• Replication

• Pathogenesis

• Cytokine Storm

• Antigen and Antibody Testing

• Treatment

• Vaccines

• Cytotoxic T-cells

• Herd Immunity

• Mouse Model

Evidence suggestive. Conclusion. Why not?