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E s :'-~,,.~~.~r~--.;:~.fi,r~ r YIRUS, PREVIOUS INFECTIONS Tme Courrcu, FOR TaE &eca RESr.Atzc$ - U.S.A. 633 1BIItD A4F.NLTE `,(,"QMT'j'F;E : NESV YORII. N: Y. 10017 Dr. Reimann, Chm4 Dr. Sotmers Dr. Jacobson Application For Research Grant #R3 Activated: 10 1 6k Renewed: 10/1/65 Renewed: 10/1/66 ` i. Name of Investigator(s): (include Titie and Degrees), :'<-Frederik B. Bang, M.D., Professor of Pathobiology :..The Johns Hopkins University School of Hygiene and Public Health 615 North Wolfe Street, Baltimore, Maryland -._ 21205 3. ShortTitle of Project: Pathogenesis of virus infections of respiratory mucosae 4. ProposedStarting Date: - To be continuous with present grant- 3. Anticipated Duration of this Specific Study: Three years r S. Brief Descripton of Objectives or Specific Aimse " l 1) Continue to study the effects of drugs and of internal and'ex- ternal environmental factors on susceptibility to viral infections, with emphasis on the initiation of infection. 2) Initiate a sequential study of regeneration and re-organization of mucosal cells following acute desquamation;"for this study, nu- clei will be labelled with tritiated thymidine, a method used exten- sively in studies of intestinal mucosae. 3) Study the effects of avitaminosis A on the susceptibility of chickens to the viruses of Newcastle disease and laryngotracheitis; we have found in~preliminary studies that avitaminosis A (known to affect mucous epithelia) shows the first apparent effects histolo- gically on the inner surface of the scroll of the maxillary concha, an area which we have found emiriently vulnerable to virus infection. 4) 1'iith the collaboration of Dr. Donald F. Proctor, we propose to determine the effects of acute upper respiratory infections on the rate of nasal mucus,clearance before, during, and after the acute clinical phase of infection; this will be a study on human volun- teers, using a method which has proved reliable in a recent study which involved several hundred tests. (Items 1, 3, and 4 will extend studies which have been primarily supported by the Council for Tobacco Research, and which have been published or are in press, as noted under item 12 below) 7. Give a Brief Statement of your Working Hypothesis: Items 7, 11; 12 are on a separate attached page `-~

X* 8. Details of Experimental Design and Procedures. (Attach Separate Pages) t'1: Drugs are administered to chicks intramuscularly or locall,r; NDV is inocu- ';labelled eells.deternined at successive time intervals. j: Chickens fed for `'bine labelling will be done in pulses, and the progress and persistence of ~fected cells is then determined by plaque techniques. 2s Tritiated thymi- >,-"cised, extensively washed, scraped, and the cells trypsini~zed; the number of. -,~rated intranasally. Chicks are killed at intervals, the maxillary conchae ex- ..;-Llnning it simultaneously with~a radioactive tracer in a series of volunteers. ;,before, during, and after spontaneous acute upper tract infection. This is ,`,~~done by injecting a chemically inert tracer dye (Direct Sky Blue, Wyeth) onto "_a particular site on the anterior mucociliated part of the nasal fossa and -timing its appearance in the nasopharynx, a method pre-tested for accuracy by -.Clearance of the upper respiratory tracts of human volunteers will be-recorded ,will be followe&by titrations and by histology. 4: The rate of mucocili'~ary lated with the two viruses and the spread of virus in the respiratory tract- :3 NeeKs arter natching on a commercial vitamin A-deprived diet-•will be inocu- r:s., ... '%°given in Item 6) ,~}(The numbers above are consistent with those of the experimental objectives 9. Physical Facilties Available (Where Other than Adlninistering Organization Indicate Geographical Location). Fully equipped virus and histological laboratories. 10. Additional Reqpirements: l) A full time histological technical trainee for routine histo- logical sectioning; the present technical assistant, Mr. Raoul Spicker, to train this apprentice and to devote most-of his own~ efforts toward autoradiography. 2) Half-time support for an additional animal man, to cover the increased use of animals requiring reliable supervision. C 11. Biographical sketches of all principal and professionat personnel (append) (appended) 12. List of publications: (Five most recent as pertinent) (append) ( app end ed') k (

. Working hypothesis 1) Alterations in the mucous-cil.iated epithelium which are induced by changes in the external and/or internal environment of '~the host will affect viral entry into mucosal cells. ~ 2} The progress of infection from cell to cell, and the re- covery of the mucous-ciliated epithelium following infection, are affected by mucous secretion. Avitaminosis A, known to induce ";conversion of mucous epithelium.to squamous epithelium, should irus infection l y myxov alter the progress of infection, particular Van-nevl vani ~_ A.B. Johns HoDkins University 1935: M.D. Johns Hop- Biogra hical sketches Frederik B. Bang, M.D., -` b. November 5, 1916 in Philadelphia x. - h ns kins School of 14iedicine 1939. Associate Professor of b7edicine, Jo :Hopkins School of Medicine 1949-1953; Professor of Pathobiology, Johns Hopkins School of Hygiene and Public Health 1953-1967. Special 'interests: virus pathogenesis; invertebrate immunology. Betsy G. Bang, A.B., - b. July 9, 1912 in Lancaster, South Carolina. A.B. George Washington University 1933; Certification in "Art as Applied to Medicine, Johns Hopxins School of Medicine 1937. Illustrator in Comparative Anatomy, American Museum Natural History 1937 - 1940; Research Associate in Pathobiology, Johns Hopkins School --'of Hygiene and Public Health 1962-1967. Specific interest: compara- tive functional anatomy of the upper respiratory tract. • Prantika Som, D.V.M., - b. August 31, 1942, Silchar, India. ll i i f 1 60 vers ; ege, Un Calcutta 9 ty o Inter-Science, Lady Bradbourne Co B.V.Sc. and A.H., and D.V.1f2. Bengal Veterinary College, University __ of Calcutta 1965. Candidate for Sc.D. degree in Department of Patho- biology, Johns Hopkins University School of Hygiene and Public Health. 12. Recent pertinent publications (1) Bang, F. B., and Foard, hi. : Interaction of respiratory epithe- lium of the chick and Newcastle disease virus. Amer. J. Hygiene 1964 79:260 - (2) Huang, J., and Bang, F.B.: The susceptibility of chick embryo skin organ cultures to influenza virus following excess vitamin A J. Exp. Med. 1964 120:129-148 (3) Bang, F. B., Bang, B. G., and Foard, M. : Responses of upper f„A respiratory mucosae to drugs and' viral infections. Amer. Review of p Resp. Dis. 1966 93:142-149 O (4) Bang, B.G., and Bang, F.B.: haryngotracheitis virus of ~ chickens: a model for acute desquamating rhinitis. J. Bxp hTed . . • 1967 125 : 4i09-4 28 (9 } Bann B G 14iukher j e e A L an(I Ban F B • Human nasal 1-1 . 0 • 1 P 0 • f .`Z) 1 . . . . . , mucus flow rates. (In press: Johns Hopkins Medical Journal) (2n press: simultaneous abstract in J. Amer. Med. Assoc.)

TECHNICAL Raoul Spicker r To be named , ieehnicaFHenry Johnson Juhan Labidas Linda Endemann Gwendolyn Futcher Research Asst. in Pathobiology Histologist Histological Tranee Animal Attendant Animal Attendant Glassware Washer Secretary . Consumabfe Supplies (list by categories) Animal Food Histological Material Publications Sub-Total C. Other Expenses Qtemize) Travel-Domestic-to attend clinics Requisition Payroll-to cover temporary summer help, termination payroll and special services .Fringe Benefits-6X--salaries and wages E. Orerhead (15%af A+$+C) Estimated Future Requirements: L.l Salaries Consumable Suppl. OtherExpenses Year 2 $21318.00 $260000 2610,00'_ Year 3 52304S.00 52600:00 2 1'.00' It is understood that the applicant and institutional officers In applying for a grant have read and found acceptable the Council's "Statement oF'Policy Containing Conditions' and?erms Uhder Whiah Project Grants Are Made." 50% $3625.00 507. 3000.00 100% ' 5000;00 88% ' ." 3060.00 507' 1500,00 1007 3645.00 12% 752.00 Sub-Total $20582.00 Sub-Total 1000.00 1000.00 600.00 800.00 Permanent'Equip. Overhead Total $1000:,00: $3980.00 $31508.00 Q $1000.00 S4254 00 $33612.00 Q Signature y l Dknaur of v,coj.ce " Telephone ~ ~~ N+ Signature tso3tnus Otfic.r of th. t.:rr.r o. Telephone VI' ~ `=

r* 'S i List financtol support for research from all sources, including own Institution, for this and/or related research projecfs. ~ I This grant to B,G, Bang finances a study of the comparative functional anatomy of the nasal folfa, t~899~SE00~ I 0 ~