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Biodefense shield and avian influenza.



To the Editor: In defending against avian influenza virus H5N1, the possibility of adopting treatments being developed for biodefense should not be overlooked. Biodefense medicine primarily concerns respiratory infections because bioweapons in their deadliest form disperse Bacillus anthracis and Yersinia pestis, the causes of anthrax and plague, and highly contagious viruses like smallpox, Ebola, and Marburg as aerosols. The National Institutes of Health and Department of Defense have funded developing novel biodefense medications designed to stimulate innate mucosal immunity by using interferons (IFNs) and interferon inducers.

We suggest that studies begin immediately to explore the potential of IFNs to prevent infections and reduce deaths caused by avian influenza viruses in animal models and humans.

Modulating innate mucosal immunity is promising as a rapid-acting, broad-spectrum approach to combat bioterrorism (1). Innate immunity, the initial response to a pathogen, is potentially capable of eradicating infection. Even when the innate immune response cannot eliminate a virus, it may substantially reduce viral load, reduce pathology, facilitate clearing of the virus by the adaptive immune response, and slow the spread of infection (1). As biodefense medications, IFNs and IFN-inducers are under development for aerosolized delivery to the lungs (2,3). Conventional IFN IFN
abbr.
interferon



IFN

interferon.

IFN Interferon, see there
 administration by injection often results in low concentrations at target sites and high concentrations in circulation, which may cause serious side effects. Aerosolized delivery minimizes side effects and produces more rapid clinical responses. Inhaled IFNs have proven to be well tolerated and beneficial for rhinovirus rhinovirus

Any of a group of picornaviruses capable of causing common colds in humans. The virus is thought to be transmitted to the upper respiratory tract by airborne droplets.
 infection (4) and pulmonary tuberculosis (5).

Medications being developed to prevent infections caused by viral bioweapons and other diseases include 1) Oral IFN-[alpha] or Alferon low dose oral (LDO LDO Low-Dropout (Used With Regulators)
LDO Limited Duty Officer
LDO Light Diesel Oil (petroleum)
LDO Local Development Officer (Nepal)
LDO Land Development Ordinance
) (Hemispherx Biopharma, Inc., Philadelphia, PA, USA); 2) inhalable IFN-[gamma] (InterMune, Brisbane, CA, USA); 3) dsRNA [Poly (ICLC ICLC International Contact Lens Clinic (journal)
ICLC Interlab Cell Line Collection
ICLC Initial Capital, Lower Case (proofreading) 
)] or Ampligen (Hemispherx Biopharma, Inc.); 4) ssRNA (Aldara and Resiquimod from 3M Pharmaceuticals, St. Paul, MN, USA); and 5) CPG CPG

central pattern generators.
7909 and CpG10101 oligonucleotides (Coley Pharmaceutical Group, Wellesley, MA, USA) (2). These drugs have either been approved by the Food and Drug Administration (FDA FDA
abbr.
Food and Drug Administration


FDA,
n.pr See Food and Drug Administration.

FDA,
n.pr the abbreviation for the Food and Drug Administration.
) (Aldara), are in clinical trials (Alferon LDO, inhalable IFN-[gamma], Resiquimod, CPG7909, and CpG10101), or at a preclinical stage of development (Ampligen). Aldara is approved for genital warts, actinic actinic /ac·tin·ic/ (ak-tin´ik) producing chemical action; said of rays of light beyond the violet end of the spectrum.

ac·tin·ic
adj.
 keratoses, and basal cell carcinoma basal cell carcinoma
n.
A slow-growing, locally invasive, but rarely metastasizing neoplasm of the skin derived from basal cells of the epidermis or hair follicles. Also called basal cell epithelioma.
. Others drugs are being tested for aerosolized delivery to modulate mucosal immunity of the respiratory tract. All could be expeditiously tested with inhalational or intranasal administration in H5N1 models with mice, ferrets, pigs, and monkeys.

IFN-[alpha] and IFN-[gamma] work by binding their receptors and activating downstream antiviral pathways involving the dsRNA-dependent protein kinase (PKR PKR

In currencies, this is the abbreviation for the Pakistani Rupee.

Notes:
The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion.
), the 2', 5' oligoadenylate synthetase/RNase L, or the MxA protein. dsRNA, ssRNA, and CpG oligonucleotides are ligands for toll-like receptors (TLRs) and modulate antiviral immunity through TLR TLR Trailer
TLR Toll Like Receptor (immunological research)
TLR Temple (University) Law Review
TLR Twin Lens Reflex
TLR Texas Law Review
TLR The Last Resort (gaming clan) 
 signaling pathways and IFN induction (2). At the cellular level inside the lungs, these drugs will enhance phagocytotic and cytolytic cytolytic

pertaining to or emanating from cytolysis.


cytolytic reactivity
type II hypersensitivity.
 activity in alveolar macrophages.

Once infection is established, H5N1 resists the antiviral effects of IFNs and tumor necrosis factor-[alpha] (6). Resistance is associated with the nonstructural gene of H5N1 and may be 1 mechanism for H5NI's extraordinary virulence. Therefore, prophylactic use of IFNs and IFN-inducers is critical to combat H5N1. They may also be effective if administered immediately after infection.

IFN resistance also exists for other viral infections. For instance, poxviruses including vaccinia virus encode 2 proteins that interfere with RNaseL and PKR pathways and 2 soluble IFN receptors that interfere with IFN-induced antiviral pathways. Nevertheless, at least in animal models, pre-infection administration of exogenous IFN can reduce deaths and poxvirus poxvirus

Any of a group of viruses responsible for a wide range of pox diseases in humans and other animals. Poxvirus was the cause of smallpox. (Human chickenpox is caused by varicella-zoster virus.
 viral load. In mice, intranasal administration of IFN-[alpha] and IFN-[gamma] prevents lethal vaccinia vac·cin·i·a
n.
1. See cowpox.

2. An infection induced in humans by inoculation with the vaccinia virus in order to confer resistance to smallpox; it is usually limited to the site of inoculation.
 infection (3). IFN-[alpha], IFN-[gamma], and an IFN inducer inducer /in·duc·er/ (in-dldbomacs´er) a molecule that causes a cell or organism to accelerate synthesis of an enzyme or sequence of enzymes in response to a developmental signal.

in·duc·er
n.
, Poly (ICLC), protect mice infected with H1N1 influenza virus (7). Hence, we suggest that anti-H5N1 prophylaxis by IFN-stimulated innate mucosal immunity is a promising therapy worth immediate investigation in animal models.

A second mechanism proposed to explain H5N1 virulence is also IFN related. This is the "cytokine storm," as shown by elevated levels of proinflammatory cytokines including IFNs found in 2 patients who died of H5N1 infections (8). Cytokine storms can result in autoimmune reactions, tissue damage, or septic shock. High IFN doses for long periods may exacerbate autoimmunity. However, despite similar cytokine storms (9), some severe acute respiratory syndrome Severe Acute Respiratory Syndrome (SARS) Definition

Severe acute respiratory syndrome (SARS) is the first emergent and highly transmissible viral disease to appear during the twenty-first century.
 patients respond well to IFN therapy (10). Optimal formulation and regimen of IFN administration could be crucial to effective anti-H5N1 prophylaxis. In the interests of safety, we propose that initial prophylaxis studies use relatively low IFN doses for short periods ([approximately equal to] 1-2 weeks).

It is unlikely that all of these drugs will effectively protect against H5N1. And a drug that is effective might not work for everyone; genetic polymorphism influences IFN response. However, FDA approval of even one of them might save many lives.

Acknowledgments

We thank Tom Hollon for his editing and helpful suggestions.

This work is funded by the Defense Advanced Research Project Agency Defense Advanced Research Project Agency - Defense Advanced Research Projects Agency .

Our company, AFG AFG Afghanistan (international vehicle registration)
AFG American Financial Group
AFG Assistance to Firefighters Grant
AFG Arbeitsförderungsgesetz (German: Labor Advancement Law)
AFG Accreditation for Growth
 Biosolutions, Inc., has no grants, contracts, or other financial support to develop a commercial antiinfluenza product from among the immunomodulators mentioned here.

References

(1). Alibek K, Lobanova C. Modulation of innate immunity to protect against biological weapon threats. In: Anderson B, Friedman H, Bendinelli M, editors. Infectious agents and pathogenesis: microorganisms and bioterrorism. New York: Springer; 2006. p. 39-61.

(2.) Amlie-Lefond C, Paz DA, Connelly MP, Huffhagle GB, Dunn KS, Whelan NT, et al. Innate immunity for biodefense: a strategy whose time has come. J Allergy Clin Immunol. 2005; 116:1334-42.

(3.) Liu G, Zhai Q, Schaffner D, Wu A, Yohannes A, Robinson T, et al. Prevention of lethal respiratory vaccinia infections in mice with interferon (IFN)-a and IFN-g. FEMS Immunol Med Microbiol. 2004;40:201-6.

(4.) Sperber SJ, Levine PA, Innes DJ, Mills SE, Hayden FG. Tolerance and efficacy of intranasal administration of recombinant beta serine serine (sĕr`ēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer appears in mammalian protein.  interferon in healthy adults. J Infect Dis. 1988;158:166-75.

(5.) Condos R, Rom WN, Schluger NW. Treatment of multidrug-resistant pulmonary tuberculosis with interferongamma via aerosol. Lancet. 1997;349: 1513-5.

(6.) Seo SH, Hoffmann E, Webster RG. Lethal H5N1 influenza viruses escape host antiviral cytokine responses. Nat Med. 2002;8:950-4.

(7.) Wong JP, Saravolac EG, Sabuda D, Levy HB, Kende M. Prophylactic and therapeutic efficacies of poly(IC.LC) against respiratory influenza A virus infection in mice. Antimicrob Agents Chemother. 1995;39: 2574-6.

(8.) To KF, Chan PK, Chan KF, Lee WK, Lam WY, Wong KF. Pathology of fatal human infection associated with avian influenza A H5NI virus. J Med Virol. 2001;63:242-6.

(9.) Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. 2005;75:185-94.

(10.) Cinatl J Jr, Michaelis M, Scholz M, Doerr HW. Role of interferons in the treatment of severe acute respiratory syndrome. Expert Opin Biol Ther. 2004;4:827 36.

Address for correspondence: Ken Alibek, National Center for Biodefense and Infectious Diseases, George Mason University Named after American revolutionary, patriot and founding father George Mason, the university was founded as a branch of the University of Virginia in 1957 and became an independent institution in 1972. , 10900 University Blvd, Manassas, VA 20110, USA; email: kalibek@gmu.edu

Ken Alibek * ([dagger]) and Ge Liu ([dagger])

* George Mason University, Manassas, Virginia, USA; and ([dagger]) AFG Biosolutions, Inc., Germantown, Maryland, USA
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Author:Liu, Ge
Publication:Emerging Infectious Diseases
Article Type:Letter to the editor
Date:May 1, 2006
Words:1186
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