Debby Hamilton, MD, MPH, is a Pediatrician with experience in primary care, integrative medicine, research, speaking and writing. Her education includes an undergraduate degree from Wesleyan University followed by a medical degree from Chicago Medical School, where she graduated with honors. She is board-certified in Pediatrics, Physician Nutrition, and Integrated/Holistic medicine (AIHM), and has a Master of Science degree in Public Health (MPH). (Altern Ther Health Med. 2020;26(S2):80-83)
With our current crisis, people are focused on masks, gloves, and hand washing to protect us from COVID-19. What about natural protection from our immune system? Nature gave us a very intricate set of checks and balances with multiple cells and messengers so that our bodies can fight the different microbes that we are exposed to everyday. One of the best defenses against the current viral pandemic is strengthening our own immune system.
Negative Effects on Our Immune System
Unfortunately, there are multiple environmental and health factors that can decrease natural immunity. Stress is a significant factor that decreases white blood cells and the ability to fight infection whether internal or from environmental factors.1 Just when we need a strong immune system to fight the COVID-19 virus, we are all under tremendous stress with our changing world and uncertainty. Luckily, by understanding how our immune system can mobilize and eliminate a viral pathogen, we can utilize treatments to strengthen this response.
Chronic health conditions can also negatively impact immunity. People with chronic autoimmune diseases have an imbalanced immune system. Often, they have elevated Th17 and Th2 lymphocyte immune responses that correspond with low Th1 responses.2,3 A low Th1 immune response will decrease a person’s ability to fight viral infections. With chronic disease there is also an elevation of chronic inflammation along with oxidative stress that can imbalance the immune system and may impact the needed acute inflammatory response to kill a pathogen. Chronic disease can range from ongoing infections such as tick-borne illness to cardiovascular disease and cancer.
Pathway of Viral infection in the body
To understand how the immune system tries to stop a viral infection, it is important to understand how a virus invades the body and triggers the immune response. Viruses have cleverly adapted to invade the human body. They also can mutate to avoid the immune system response.
Most viruses enter our body through our respiratory and digestive systems. Through these tissues they can invade cells and release their genetic material, either RNA or DNA. This genetic material invades the cell nucleus where it uses the host cell to create additional genetic material that becomes new viruses. These are then released from the host cell to invade new cells and continue the viral infection. Sometimes these host cells are destroyed in the process.
Unique Sars-CoV2 virus infection in the body.
The Sars-CoV2 virus, which causes the COVID-19 infection, has specific mechanisms for invading the body. These are different time points in the body where the immune system can try to decrease the invasion from the virus. Specific natural treatments can interfere with different stages in the development of infection to help lessen the impact of the virus.
The Sars-Cov2 virus attaches to the ACE2 receptor whose role is to breakdown angiotensin. High amounts of ACE2 receptors are found in the lungs, kidney, cardiovascular system, digestive system and the vascular endothelium which correlate with symptoms seen in the disease.4 Once the virus is bound to the receptor, the furin protein cleaves the envelope protein which activates the virus and allows its entry into the cell.5 The 3C protease enzyme then breaks down the peptides from the translated viral RNA that are needed for viral replication.6 The virus uses the mTOR pathway of the cell for viral replication.7 Finally, the virus codes for viroporins which code for channels in the cell membranes for the virus to exit the cell and continue to invade other cells.8
The Sars-CoV2 virus appears to have two mechanisms to evade activation of the innate immune system which leads to poorer activation of the adaptive immune system and expansion of T cell lymphocytes. Delayed type 1 interferon signaling leads to a delay in initiating the innate immune response. The virus also seems to be able to delay macrophage and dendritic cell response.9 When trying to improve immunity to the Sars-CoV2 virus, supporting a strong innate immune response is important for both early immune protection and long-term protection from the adaptive immune system.
Exposure to infection comes primarily through our respiratory and digestive tracts. Even if we encounter a microbe on our hand, the microbe is transferred to either our mouth or nose to enter our body. Both these systems are lined with a first line protective barrier against infection. This epithelial lining contains immune cells that are triggered and begin the immediate innate immune system reaction. An increase in blood flow also brings immune cells toward the site of infection.
There are multiple immune cells that are part of the innate immune response. For viruses, there are several important cells including natural killer cells (NK cells), neutrophils, macrophages and dendritic or antigen presenting cells (APC). Interferon is a cytokine released from viral infected cells that tries to prevent viral replication. It is also a signaling molecule for nearby cells that there is a viral infection.
An essential early response to viral infection is from NK cells to help with clearance of these cells. Their primary role is to kill viral infected cells. These cells also release multiple cytokines and chemokines that interact with other cells playing a role in immune homeostasis. In the lungs, the NK cells are the primary cell making up 10-20% of the overall lymphocytes, therefore critical for the SARS-CoV2 virus which invades the lungs.10 As their name suggests, the NK cell role is to destroy the virally infected cells. They do this through the release of cytolytic granules that enter the infected cell and trigger apoptosis or death of the cell.11 Increasing the number and function of NK cells is a critical step in improving immunity to viral infections.
Natural killer cells are also cytotoxic by releasing proteins called perforin that form holes in the cell membrane where granzymes enter to destroy the virus inside the cell. NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while the adaptive immune response is generating antigen-specific cytotoxic T cells that can clear the infection.
With the onset of an infection, neutrophils, which are abundant in the blood are rapidly recruited to the site of infection. They have toll like receptors that sense pathogens. Neutrophils are phagocytic and release lytic enzymes from their granules which create free radicals. Many of the chemicals they release can be toxic to normal cells if they remain in the tissues for too long or if too many cells are called in to fight the infection. They are traditionally considered acute inflammatory cells of the innate immune system so are essential for the initial response. Research into neutrophils is showing increased roles for the cell in the immune response including having a bidirectional role between regulating the innate and adaptive immune responses.12,13 To activate B cells and the humoral adaptive immune response, they make cytokines to help in B cell maturation. They also make neutrophil extracellular traps (NET) that have DNA and protein from neutrophil granules that trap microorganisms.12,13
Macrophages are derived from monocytes in the peripheral system. Their role is to ingest the offending microbe as part of the initial inflammatory response of the innate immune system. In addition, they are part of the mechanism to stop inflammation by consuming debris and cells such as neutrophils that have already released their lytic enzymes.14 After ingesting a microbe, the macrophage displays an MHC antigen on its surface that starts the development of the T and B cell adaptive immune response. Dendritic cells (antigen presenting cells), like macrophages are myeloid cells that are part of the first line immune defense. When the body has an initial infection, monocytes are recruited to the site of the infection and give rise to the different myeloid subsets including dendritic cells. Their role is to activate t-lymphocytes to begin the adaptive immune response.15
For long term protection from repeated infections, the adaptive immune system after the first infection provides memory for subsequent infections. This system is activated by the innate immune system by a three-signal control mechanism. An antigen bound to the innate immune cells activates the T cell receptor and causes an increase in antigen specific T cells.16 When an antigen presenting cell is associated with a PAMP (Pathogen associated molecular pattern) this signal provides co-activation of the cells to help with identifying self-versus non self-antigens.16 Finally, innate immune cell cytokines help the T cells differentiate into T cell subsets.16
There are multiple types of T cells including several different types of T helper cells and cytotoxic T cells. All the lymphocytes are increased with the activation of the adaptive immune response. One of the critical cells for viral immunity is the production of Thelper 1 cells (Th1). A strong Th1 immune response is critical for viral clearance. Understanding this fact helps us develop strategies for strengthening this response. The Th1 cells are involved in cell mediated immunity. They release transfer factors which bind to the antigen on the infected cell identifying it to be destroyed by cytotoxic CD8 T cells.
Th2 cells are also induced by an infected phagocytic cell along with the activation of B cells. Both lymphocytes are involved in humoral mediated immunity. The Th2 cells are designed to help with extracellular pathogens such as bacteria where Th1 cells target intracellular organisms such as viruses. B cells once activated produce antibodies that bind to antigens on infected cells in a similar manner to transfer factors from activated T cells.
Since our bodies are designed to fight viruses, the most important thing we can do now is to strengthen this system. We need to strengthen both the innate and the adaptive immune systems. Without a strong innate immune system, there is inadequate activation of the adaptive immune system with insufficient number of lymphocytes. Natural killer cells are a key component of the innate viral response so enhancing not only their numbers, but function is important. A strong innate response is important to activate the Th1 cell mediated immune response needed for viral elimination. Nature has given us many herbs and natural components from colostrum that can be safely used to enhance our immune system’s ability to fight viruses.
Transfer factors are small proteins with genetic material that are made by activated T helper cells as part of the adaptive immune response. These are similar but smaller than the immunoglobulins produced by B cells as part of the humoral mediated immune response.
A strong Th1 response is critical to fight a viral infection and transfer factors play a key role in this adaptive cell mediated response. Once the innate immune system is activated a macrophage develops an antigen marker on its surface after engulfing a virally infected cell. The macrophage also releases cytokines to notify Th1 cells to begin the cell mediated response which includes releasing transfer factors and Th1 cytokines. This process leads to an increase in new Th1 CD4 cells, cytotoxic T CD8 cells, natural killer cells, and macrophages.17,18 The role of the transfer factors is to bind to antigens on an infected body cell to target the cell for destruction by the CD8 toxic T cells. Since part of this process is to increase natural killer cells, this provides a feedback loop to further increase the innate immune response to further contain the growth of the viral infection.
Transfer factors help fight viral infections by both increasing natural killer cells and strengthening a Th1 immune response.17,18 Therefore, they are key to preventing and treating viral infections. They are also very helpful for early viral infections to support both the innate and adaptive immune systems. As a supplement, they are usually derived from colostrum although they can also be derived from the serum from white blood cells. Transfer factors from other mammalian species are similar which makes them a safe option.
With autoimmune disease and chronic inflammatory disease, it is common for decreased Th1 immune responses to correlate with an elevated Th17 inflammatory response which leads to autoimmune disease and chronic disease states. This often correlates with an increased Th2 system leading to more allergies and mast cell responses. Increasing the Th1 immune response can also help balance the immune system in many people with chronic disease and autoimmune disease.
In integrative medicine, glutathione is well known as our master antioxidant needed to decrease free radicals. High amounts of glutathione are in the liver where it is needed to help detoxify chemicals. What is not as well known is that high amounts of glutathione are also needed in the lungs. Decreased amounts of glutathione in the lungs are seen with many chronic lung diseases such as COPD, ARDS (which is seen with COVID-19), Cystic Fibrosis and lung infections.19 It makes sense if there is an excess of free radicals from the lack of glutathione that the lung would be susceptible to oxidative stress damage.
One of the other functions not as well known about glutathione is its role in promoting natural killer cell function.19 It also has a role in enhancing T cell function.19 Enhancing these parts of the immune system will help eliminate viral pathogens. If glutathione is low in the lungs, this can be an important supplement to include to build lung stores where the COVID-19 infection is prominent while improving viral immune support. Research studies with supplemental glutathione have found increases in natural killer cell function supporting the use of oral liposomal glutathione helping immune function.20
Astragalus (Radix astragali)
Astragalus is a commonly used herb in traditional Chinese medicine. It has been used for prevention and treatment of coronavirus infections.21 The herb has multiple immunomodulatory effects on both the innate and adaptive immune systems. For viral infection immune support, it increases natural killer cell activity and promotes a stronger Th1 response.22,23 While increasing the Th1 cell mediated immune response, it also decreases the Th2 response which contributes to allergic responses and mast cell activation promoting immune system balance.24 Decreasing the Th2 response in a person with COVID-19 can also help decrease inflammation which if elevated can lead to serious detrimental outcomes later in the disease progression.
Andrographis (Andrographis paniculate)
For immunomodulatory effects, Andrographis is another important herb. It has been shown to have a wide multitude of effects including enhancing natural killer cells, cytotoxic T cells, phagocytosis and antibody dependent cell mediated cytotoxicity.25 With its multiple actions on the immune system, it strengthens immunity against viruses, bacteria, and parasites.25 By decreasing cytokines, it also has an anti-inflammatory effect.26 Overall a good herb for COVID-19 from fighting the viral infection to decreasing some of the excessive inflammation
With the spread of the new Sars-COv2 virus, it has become clear that our own immune defenses are the best tools we have to prevent and fight this virus. Critically important are to strengthen both the innate and adaptive immune systems which work together to coordinate this immune response. For viral infection, critically important components such as the natural killer cells and the Th1 adaptive immune response must be supported. Decreasing stress and a healthy whole foods diet are important along with targeted supplements to optimize our own best defense.
- Glaser R. Stress-associated immune dysregulation and its importance for human health: A personal history of psychoneuroimmunology. Brain Behav Immun. 2005. 19(1):3-11.
- Gol-Ara M. et al. The role of different subsets of regulatory T cells in immunopathogenesis of rheumatoid arthritis. Arthritis. 2012;2012:805875.
- Vitales-Noyola M. et al. Pathogenic Th17 and Th22 cells are increased in patients with autoimmune thyroid disorders. Endocrine. 2017 Sep;57(3):409-417.
- Hamming I. et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631‐637.
- Coutard B. et al. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020;176:104742.
- Báez-Santos YM. et al. The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral Res. 2015;115:21‐38.
- Zheng Y. et al. Immunoregulation with mTOR inhibitors to prevent COVID19 severity: A novel intervention strategy beyond vaccines and specific anti-viral medicines. J. Med Virol.
- Castaño-Rodriguez C.et al. Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis. mBio. 2018;9(3):e02325-17.
- Prompetchara E. et al. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020 Mar;38(1):1-9.
- Bjorkestrom NK. et al. Emerging insight into natural killer cells in human peripheral tissues. Rev. Immunol. 2016. 16(5):310-20.
- VanErp EA. et al. Viral infection of human natural killer cells. 2019.
- Mantovani A. et al. Neutrophils in the activation and regulation of innate and adaptive immunity. Rev. Immunol. 2011. 11(8): 519-31.
- Teng TS. Et al. Neutrophils and immunity: From bactericidal action to being conquered. of Imm. Res. 2017.
- Essandoh K. et al.MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response. Shock. 2016;46(2):122‐131.
- Wacleche VS. et al.The Biology of Monocytes and Dendritic Cells: Contribution to HIV Pathogenesis. Viruses. 2018;10(2):65.
- Jain A, Pasare C. Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm. J Immunol. 2017;198(10):3791‐3800.
- Viza D. et al. Transfer Factor: an overlooked potential for the prevention and treatment of infectious diseases. Folia Biologica. 59, 53-67.
- Lawrence HS: Transfer factor in cellular immunity. The Harvey Lecture Series 68. New York: Academic Press, 1987.
- Ghezzi P. Role of glutathione in immunity and inflammation in the lung. Int J Gen Med. 2011;4:105–113.
- Sinha et al. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Jr. Of Clin Nutr. 2017
- Luo H. et al.Can Chinese Medicine Be Used for Prevention of Corona Virus Disease 2019 (COVID-19)? A Review of Historical Classics, Research Evidence and Current Prevention Programs. Chin J Integr Med. 2020 Apr;26(4):243-250.
- Zheng Y. et al. A Review of the Pharmacological Action of Astragalus Polysaccharide. Front Pharmacol. 2020;11:349. Published 2020 Mar 24.
- Li ZX. Et al. Immunomodulatory effects of a new whole ingredients extract from Astragalus: a combined evaluation on chemistry and pharmacology. Med. 2019;14:12.
- Chen SM. et al. Astragalus membranaceus modulates Th1/2 immune balance and activates PPARγ in a murine asthma model. Biochem Cell Biol. 2014 Oct;92(5):397-405.
- Gupta S. et al. Broad-spectrum anti-viral properties of andrographolide Arch Virol. 162:611-623.
- Parichatikanond W. et al. Study of anti-inflammatory activities of the pure compounds from Andrographis paniculata (burm.f.) Nees and their effects on gene expression. Int Immunopharmacol. 2010 Nov;10(11):1361-73.